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\title{Tourette syndrome research highlights from 2020}
\author[1]{Andreas Hartmann}%
\author[2]{Cyril Atkinson-Clement}%
\author[3]{Christel Depienne}%
\author[4]{Kevin J. Black}%
\affil[1]{Sorbonne University, National Reference Centre for Tourette Disorder, Pitié-Salpêtrière Hospital, Paris, France}%
\affil[2]{Institut du Cerveau et de la Moelle Épinière}%
\affil[3]{University of Duisburg-Essen}%
\affil[4]{Washington University in St. Louis}%
\vspace{-1em}
\date{March 29, 2024}
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\selectlanguage{ngerman}\emph{Copyright ©~2020-2021, the authors.~}AH:
ORCiD~0000-0002-0335-984X;~CA-C: ORCiD~0000-0001-9499-3485;~CD:
ORCiD~0000-0002-7212-9554;~KJB: ORCiD 0000-0002-6921-9567
\textbf{{This article has been submitted to F1000Research. Please
suggest~}\href{https://www.authorea.com/509057}{{articles from 2021
here}}{. Feel free to suggest your own work as well as others'.}}
\section*{Abstract}
{\label{958993}}
We present here~research from 2020 relevant to Tourette syndrome (TS).
The authors briefly summarize a few reports they consider most important
or interesting.~
\section*{Introduction}
{\label{876427}}
This article is meant to disseminate recent scientific progress on TS.
\section*{Methods}
{\label{579451}}
We searched PubMed during 2020 using the search strategy~\emph{(``Tic
Disorders''{[}MeSH{]} OR Tourette NOT Tourette{[}AU{]}) AND
2020{[}PDAT{]} NOT 1950:2019{[}PDAT{]}}. On 15 Feb 2021 this
search~\href{https://pubmed.ncbi.nlm.nih.gov/collections/59214852/?sort=pubdate}{returned
292 citations}. Colleagues also recommended articles, and we attended
selected medical conferences (in 2020, mostly online) . We selected
material for this review subjectively, guided by our judgment of
possible future impact on the field.
\section*{Results}
{\label{594032}}
\subsection*{Phenomenology and natural
history}
{\label{520534}}
Health-related quality of life in 52 adults with TS was explained
largely (79\% of variance) by four self-report questionnaires measuring
severity of depression, anxiety, obsessive-compulsive symptoms, and
ADHD, plus the total tic score (TTS) from the YGTSS~\hyperref[csl:1]{(Isaacs et al. 2021)}.
Depressive symptoms were the strongest predictor by far, and TTS was the
weakest. This result supports previous studies concluding that attending
to non-tic psychiatric symptoms is crucial in providing optimal care for
tic patients.
Three German centers drew attention to a spate of patients presenting
with unusual, tic-like manifestations that appeared to be driven by a
prominent social media influencer~\hyperref[csl:2]{(Müller-Vahl et al. 2020)}.~
\subsubsection*{COVID-19}
Because of the outbreak of SARS-CoV-2,~the medical landscape shifted
significantly in 2020. One consequence was the widespread deployment of
telemedicine services, which was discussed specifically for TS by Cen et
al.~\hyperref[csl:3]{(Cen et al. 2020)}.~
At the beginning of the pandemic (spring 2020) worries and concerns were
raised how this could impact people with TS, albeit on a speculative
basis~\hyperref[csl:4]{(Robertson et al. 2020)}. Studies published later in the year sought to
investigate this.~In an Italian cohort, and rather unsurprisingly,
lockdown worsened symptoms in a majority of patients with TS (n=238),
ranging from tics to hyperactivity, rage attacks, obsessions/compulsions
and anxiety. Of note, however, about one fifth of patients reported
symptom improvement, maybe linked to lessened social
exposure~\hyperref[csl:5]{(Conte et al. 2020)}. Similar observations were made by two
further groups~\hyperref[csl:6]{(Graziola et al. 2020)}\hyperref[csl:7]{(Mataix-Cols et al. 2020)}.
\subsubsection*{\texorpdfstring{{Epidemiology}}{Epidemiology}}
{\label{997451}}
Another analysis of the Swedish population registry revealed
significantly more substance abuse and consequences---including
substance-related death---in people with TS~\hyperref[csl:8]{(Virtanen et al. 2021)}. This
result was not explained by other psychiatric illness nor by familial
effects (assessed by comparison with their siblings without TS). This
result adds substance-related death to suicide and accidental deaths
previously found by this same group to be elevated in TS, and suggests
clinicians should assess substance use in patients and arrange
appropriate treatment. From the same group, it was shown that serious
transport accidents occur more frequently in people with TS/CTD but that
this is largely explained by comorbid ADHD~\hyperref[csl:9]{(Mataix-Cols et al. 2021)}. Finally,
Fernández de la Cruz and Mataix-Cols review the emerging data on higher
rates of general medical illness and mortality in TS based on their
comprehensive work using the afore-mentioned Swedish population
registry~~\hyperref[csl:10]{(Fernández and Mataix-Cols 2020)}.
The question whether the prevalence of TS might vary across the globe
remains open. Previous studies suggested that TS might be rarer in
Sub-Saharian Africa (also Japan) than in North America and Europe, where
most epidemiological studies have been conducted so far. Rodin et al.
challenge this assumption, rather proposing that adequate training and
increased public awareness might result in higher recognition of TS in
Uganda and elsewhere. This seems to be a sensible proposition, given
that TS was considered ultra-rare just a few decades ago in~North
America and Europe~\hyperref[csl:11]{(Rodin et al. 2021)}. ~
\subsubsection*{Sensory phenomena and premonitory
urges}
{\label{707888}}
In 61 people with TS, being aware of signals for emerging tics (quality
and intensity of premonitory urges) seems to facilitate self-initiated
tic suppression, while ruminative tic-associated sensations did not,
which lends support to the use of premonitory urges in behavior therapy
of tics~\hyperref[csl:12]{(Matsuda et al. 2020)}
Sensory hypersensitivity is a frequent feature in patients with TS and
should not be associated uniquely or primarily with autism spectrum
disorder. In 34 adults with TS, Isaacs et al. confirm what had
previously been described mostly in youth with TS, and they further show
that sensory hypersensitivity is associated with obsessive-compulsive
symptom severity~\hyperref[csl:13]{(Isaacs et al. 2020)}. By the same group, a comprehensive
review on this topic with an accent on pathophysiology of sensory
processing dysfunction in TS and associated
disorders~\hyperref[csl:14]{(Isaacs and Riordan 2020)} .
A revised version of the PUTS (Premonitory Urges for Tic Disorders Scale
- PUTS-R) was proposed by Baumung et al., with slight rephrasing
compared to the original, and divided into two subscales regarding urge
severity and urge quality~\hyperref[csl:15]{(Baumung et al. 2021)}. Also, the psychometric
properties of the original scale were tested in a very large cohort of
children (n=658, subdivided into three age groups: 3 to 7 years, 8 to 10
years, 11 to 16 years) within the EMTICS study. Contrary to previous
findings, the PUTS also displayed good internal reliability in children
under the age of 10. In children 11 years or older, sensory phenomena
related to tics and mental phenomena observed in obsessive-compulsive
disorder could be distinguished. The authors conclude that
questionnaires assessing premonitory urges might need to be
age-specific~\hyperref[csl:16]{(Openneer et al. 2020)}.~
\subsubsection*{Other}
{\label{754022}}
Emotional dysregulation is frequently observed in TS and thought to be
related to the co-occurence of ADHD, eventually predisposing to
explosive outbursts. However, it has has so far been mostly~assessed in
parent-reported questionnaires. Using an observational measure, Hagstrøm
et al. directly examined children with TS only, ADHD only, TS+ADHD, and
controls. Emotional dysregulation was clearly dependent on the presence
of ADHD and could not be observed in TS only~\hyperref[csl:17]{(Hagstrøm et al. 2021)}.~
A well-written and comprehensive review on one of the foremost
therapeutic challenges in TS, i.e., rage attacks: many questions remain
open and much work needs to be done~\hyperref[csl:18]{(Conte et al. 2020)}. On this topic,
Müller-Vahl et al. propose a revised version of their Rage Attack
Questionnaire for adults, this becoming the RAQ-R. Testing this new tool
in 127 patients with TS (compared to 645 controls), it was found that
rage attacks correlated with and ADHD but, interestingly, could also be
observed in ``TS only'' patients~\hyperref[csl:19]{(Müller-Vahl et al. 2019)}.
Aggressive symptoms in youths with TS (n=47, compared to 32 controls)
appear to correlate with the severity of ADHD; overall, there was -
somewhat surprisingly - no difference between the TS and the control
group. Note, however, that agression and rage attacks may be correlated
but are not identical entities \hyperref[csl:20]{(Benaroya-Milshtein et al. 2020)}.~
Two up-to-date and complete review of sleep disorders in TS appeared,
covering both adults and
children~\hyperref[csl:21]{(Jiménez-Jiménez et al. 2020)}\hyperref[csl:22]{(Hibberd et al. 2020)}. Importantly,
self-injurious behavior in TS was comprehensively reviewed by Stafford
and Cavanna~\hyperref[csl:23]{(Stafford and Cavanna 2020)}.
Openneer and colleagues studied a cognitive control task in children
with TS, ADHD, neither or both~\hyperref[csl:24]{(Openneer et al. 2019)}. Their results
suggest that executive control impairment in TS could be explained by
ADHD, not the tic disorder itself.
Kurvits and colleagues present a wonderfully thorough and thoughtful
review of disinhibition as a unifying summary of tics and more complex
symptoms in TS~\hyperref[csl:25]{(Kurvits et al. 2020)}. They note strengths and weaknesses
of this formulation and suggest future studies that may help resolve the
debate.
A large study (N=720) compared compared autistic and compulsive
phenomena in children with a clinical diagnosis of either TS or
ASD~\hyperref[csl:26]{(Gulisano et al. 2020)}. The CY-BOCS for ASD measure was abnormal in
patients with ASD or TS+ASD, but not in TS patients without ASD. Low and
high scores successfully separated ASD from non-ASD, with or without TS,
but scores between 1 and 14 on the CY-BOCS ASD did not adequately
discriminate the two groups.
\subsection*{Etiology}
{\label{984198}}
\subsubsection*{Genetics}
{\label{250980}}
Despite several studies published in 2020, the genetic factors
contributing to TS remain largely unknown. These studies are divided
into three main approaches: 1) whole exome sequencing (WES) and 2)
microarrays, which aim to identify rare coding variants or copy number
variants with large effects while 3) association studies mainly focus on
common variants. WES sequencing in a Chinese family with several
affected members identified a missense variant in~\emph{CLCN2} (G161S),
which was enriched in a TS cohort~\hyperref[csl:27]{(Yuan et al. 2020)}. Loss-of-function
variants in~\emph{CLCN2}, encoding the CLC-2 chloride channel, cause a
leukoencephalopathy with ataxia, a recessive monogenic
disorder~\hyperref[csl:28]{(Depienne et al. 2013)}. The association of G161S with TS remain to
be confirmed and its functional impact on the channel investigated.
Another WES study conducted on 15 Chinese child-parent trios led to the
identification of 25 coding~de novo~variants including two that likely
disrupt gene function. The same study also identified rare compound
heterozygous variants in~\emph{CELSR3} in one
proband~\hyperref[csl:29]{(Zhao et al. 2020)}.~\emph{CELSR3} encodes the Cadherin EGF LAG
seven-pass G-type receptor 3 that may have an important role in
cell/cell signaling during nervous system formation and is one of the
few genes significantly associated with TS using
WES~\hyperref[csl:30]{(Wang et al. 2018)}\hyperref[csl:31]{(Willsey et al. 2017)}. A review by~{Zhang and
colleagues~}highlighted the possible role of variants in~\emph{ASH1L} in
the etiology of psychiatric disorders including TS, autism spectrum
disorders and intellectual disability~\hyperref[csl:32]{(Zhang et al. 2021)}.~\emph{ASH1L}
encodes a histone-lysine N-methyltransferase specifically trimethylating
Lysine 36 of histone H3 forming H3K36me3. De novo mutations in this gene
mainly cause intellectual disability with autistic
traits~\hyperref[csl:33]{(Krumm et al. 2015)}. A single study making use of Array CGH
identified a 260-kb duplication on chromosome Xq28 comprising two genes
(\emph{VAMP7} et~\emph{SPRY3}) in a single female patient, inherited
from her healthy father. The same duplication has been reported many
times as likely benign in Decipher and do not lead to increase
expression of the gene in blood, thus association with TS remains
speculative. Several association studies focused on candidate genes or
candidate regions have suggested possible association of rare or common
variants in~\emph{CNR1} (cannabinoid receptor 1),~\emph{LHX6, IMMP2L}
and~\emph{AADAC} with TS~\hyperref[csl:34]{(Szejko et al. 2020)}~\hyperref[csl:35]{(Pagliaroli et al. 2020)}. These
association studies were performed on case-control populations limited
in size and need further replication. Furthermore, a study showed that
deletions altering~\emph{IMMP2L} (encoding the mitochondrial inner
membrane protease subunit 2) do not lead to a substantial mitochondrial
dysfunction in fibroblasts of TS subjects, thus questioning the
biological relevance of variants in this gene~\hyperref[csl:36]{(Bjerregaard et al. 2020)}.
Finally, a recent study showed that socioeconomic status and education
have to be taken into account when studying genetic factors involved in
TS as these constitute potential confounders limiting the power of
current genetic studies~studies~\hyperref[csl:37]{(Wendt et al. 2021)}. ~
\par\null\par\null
\subsubsection*{Environmental risk
factors}
{\label{429545}}
A monumental and definitive review (for the time being) on the
immunology (immune pathways, neuroinflammation, microbiome) of brain
development in general and TS in particular was written by one of the
foremost specialists in the field~\hyperref[csl:38]{(Martino et al. 2020)}.~
A fascinating study was driven by the clinical observation that blinking
tics, a common first symptom of tic disorder, are often mistaken for
allergic conjunctivitis (AC) by families and primary care physicians. A
group in southwest China studied 70 children with Provisional Tic
Disorder (PTD) and 70 tic-free controls and found that AC was more than
4 times more common in PTD (74\%) than controls
(17\%)~\hyperref[csl:39]{(Chen et al. 2020)}. They showed it could not all be symptom
confusion, as quantitative measures of dry eyes and allergic responses
to a skin prick test were also about 4 times more common in PTD. These
results suggest interesting ideas about immune abnormalities leading to
tics. We suggest another possibility based on the common patient report
that tics developed after a behavior repeated for another reason
outlived its provoking stimulus and became chronic, e.g. a child coughed
due to an upper airway infection, but then the cough persisted and
became a tic. Perhaps sometimes tics develop when underlying host
factors turn an externally-triggered repeated behavior (like blinking or
coughing) into a chronic symptom; previously, a rodent study showed that
this two-hit scenario could cause a different movement disorder,
dystonia~\hyperref[csl:40]{(Schicatano et al. 1997)}.
\subsection*{Pathophysiology}
{\label{164959}}
\subsubsection*{Animal models}
{\label{182932}}
Recanatesi et al. offer the interesting observation that sequences of
self-initiated movements can be phenomenologically consistent but their
timing may differ substantially from one instance of a sequence to
another \hyperref[csl:41]{(Recanatesi et al. 2020}; \hyperref[csl:42]{Recanatesi et al. 2021)}. They used a rat model and cortical
electrical recordings to inform a hidden Markov model. They showed that
a model ``produced by reciprocally coupling a high dimensional recurrent
network and a low dimensional feedforward one'' can produce certain
``metastable attractors'' with both predictable phenomenological
patterns but highly variable timing. Since tics~ also often occur in
stable sequences, a similar model may provide useful, testable
hypotheses for how the brain generates such tic sequences. ~
\subsubsection*{Electrophysiology}
{\label{238265}}
Cagle and colleagues reported an interesting study based on LFP
recording of both the centromedian thalamic nucleus and the primary
motor cortex in 4 TS patients following bilateral deep brain stimulation
surgery \hyperref[csl:43]{(Cagle et al. 2020)}. They highlighted that beta power (12-30Hz)
was reduced in the primary motor cortex after both a tic and a voluntary
action, while low-frequency power (3-10Hz) was increased after a tic but
not after a voluntary movement. They concluded to the identification of
a tics' specific signal within the centromedian thalamic nucleus which
could be a target for developing closed-loop deep brain stimulation.
A vast resting-state EEG study comparing young (7-15 years old) TS
patients, chronic tic disorders patients and healthy controls revealed
many interesting results \hyperref[csl:44]{(Naro et al. 2020)}. Among them, they
highlighted a disconnection of the fronto-parietal network which could
contribute to TS motor symptomatology, while a sensorimotor
disconnection was revealed for both TS and chronic tic disorders
patients as related to tic severity only. In addition, they identified
the dynamic of tics in both groups of patients as follow: (1) for TS
patients only, tics are preceded by a gamma (30-70Hz) frequency
activation and a beta2 (20-30Hz) frequency deactivation in the posterior
cingulate cortex and the supplementary motor area; (2) for both, tics
onset are associated with alpha (8-13Hz) and beta (13-30Hz) deactivation
within the sensorimotor areas; (3) for TS patients only, tics are
followed by a gamma (30-70Hz) and beta (13-30Hz) frequency activation in
the left dorsolateral prefrontal cortex, while for chronic tic disorders
patients they are followed by a delta (2-4Hz) and alpha (8-13Hz)
deactivation within the posterior cingulate cortex. Therefore, the
dynamic of tics in TS and chronic tic disorders patients are differently
disturbed, and the fronto-parietal network disconnection result
reinforces the known pathophysiology of TS as related to an impairment
of the limbic, paralimbic and cortico-striatal-thalamo-cortical
pathways.
Sun and colleagues explored the suppressive effect of the motor system
on the sensory system in TS patients \hyperref[csl:45]{(Sun et al. 2020)}. They used a
sham-controlled rTMS protocol (1Hz, 90\% of the resting motor threshold)
and recorded the somatosensory evoked potentials before and 15 minutes
after rTMS. If somatosensory evoked potentials amplitudes were decreased
for both TS patients and healthy controls, the decrease was stronger for
TS patients. They interpreted this finding as a suppressive effect of
the motor-sensory system on the sensory system instead of a sole
influence of the motor system, and therefore as TS resulting more from a
sensorimotor disorder than a sole motor dysfunction.
\subsubsection*{Neuroimaging studies}
{\label{238265}}
Rae and colleagues provide a high-quality study of action inhibition in
TS~comprising 23 adults with TS and 21 healthy controls using the same
intentional inhibition task ~\hyperref[csl:46]{(Rae et al. 2020)}.~ Importantly, the
authors chose a task that did not directly involve tics, so both groups
could participate equally in inhibiting a movement. Several inhibitory
regions were more active in TS, especially right inferior frontal gyrus,
plus insula and basal ganglia. Even though participants did not move,
the primary cortex was more active during the task in the TS group but
less active in the control group. Finally, during a task in which
participants decide on their own whether or not to move a finger,
premonitory sensations correlated with functional connectivity of the
pre-SMA region to caudate, globus pallidus and thalamus.
Hippocampal volume was increased both in TS and in 41 children with
provisional tic disorder (PTD) compared to tic-free control
children~\hyperref[csl:47]{(Kim et al. 2020)}. Since the PTD group was studied a mean of
only 4 months after~ tic onset, this difference cannot be due to living
with or adapting to tics for years, an advantage over all studies in TS
itself. Excitingly, in the PTD group, a larger hippocampus at the
initial visit predicted worse tic severity at one-year follow-up,
comprising the first predictive biomarker identified for
PTD~\hyperref[csl:47]{(Kim et al. 2020)}. Surprisingly, striatal volume at baseline did
not predict tic severity at follow-up.
Bhikram and colleagues reported a resting-state fMRI study in TS~ that
included 39 TS patients and 20 controls, analyzed using~ seed-based
functional connectivity (fcMRI) methods~\hyperref[csl:48]{(Bhikram et al. 2020)}. The TS group
showed greater connectivity between the temporal gyri, insula and
putamen, and between orbital frontal cortex (OFC) and cingulate
cortex.~Tic severity correlated with increased connectivity of the
putamen with sensorimotor cortex. By contrast, OCD severity correlated
with decresae connectivity between SMA and thalamus and between caudate
and precuneus.~Finally, premonitory urge severity correlated with
decreased connectivity between OFC and primary sensorimotor cortext, and
inferior frontal gyrus correlated with putamen and insula. Perhaps
surprisingly, even though only the first symptom domain reflects actual
movement, all three symptom-related networks include sensorimotor
regions.
Zapparoli and colleagues reported two interesting studies of the
experience of agency,~\emph{i.e.} the appreciation that we intentionally
acted and our actions caused the observed
consequences~\hyperref[csl:49]{(Zapparoli et al. 2020}; \hyperref[csl:50]{Zapparoli et al. 2020)}.~{These studies} involved 25 adults with
TS and 25 tic-free control participants, and used an implicit, indirect
measure of agency called the intentional binding phenomenon, in which
people judge the delay between an action (\emph{e.g.,} pressing a
button) and its effect (\emph{e.g.,} the turning on of a light) to be
shorter with intentional than with passive movement. The earlier report
gives results from tic-free participants studied with fMRI and TMS to
the pre-supplementary motor area (pre-SMA). The second report shows that
the TS group did not show significant intentional binding or correlation
with activity in the network identified in the control group. The
authors interpret the results as consistent with impaired action
monitoring and an impaired sense of agency in TS, which may contribute
to the perception of some people with TS that tics are fully
involuntary.
``Rage attacks'' in TS were examined using structural and functional MRI
network methods in 55 patients with TS, 47\% of whom had intermittent
explosive outbursts (IEOs)~\hyperref[csl:51]{(Atkinson-Clement et al. 2020)}.~The group with IEOs
(TS+IEO) was compared to the remaining (TS\selectlanguage{english}-IEO) group, and showed
increased fractional anisotropy in the right SMA and right hippocampus,
and decreased mean diffusivity in the left OFC.~Those 3 regions were
used as seeds for resting state fcMRI. The TS+IEO group showed lower
connectivity within a sensorimotor cortical-basal ganglia network, and
altered connectivity among OFC, amygdala and hippocampus.~These results
suggest that IEOs are associated in TS with disrupted white matter and
associated functional connectivity in circuits related to action
selection, emotion regulation, impulse control, and aggression.
Using diffusion tensor imaging and subcortical regions of interest in 15
children suffering from TS and 15 healthy controls, Xia and colleagues
found decreased fractional anisotropy (FA, related to white matter
myelin integrity, fiber compactness and parallelism) in the left globus
pallidus and the left thalamus and an increased apparent diffusion
coefficient (ADC, related to the molecular diffusion rate) increased in
the right caudate nucleus and the thalamus bilaterally in TS
patients~\hyperref[csl:52]{(Xia et al. 2020)}. Moreover, the decreased FA within the left
thalamus was related to the YGTSS score.
An MRI surface-based study on an important sample of 60 TS patients and
52 healthy controls was also published this year \hyperref[csl:53]{(Kong et al. 2020)}.
They identified several changes regarding cortical thickness and
cortical curvatures, essentially distributed within the frontal,
parietal and temporal cortices, but they found no difference regarding
local gyrification.
Frequency-specific regional homogeneity (ReHo) was also assessed in
children's patients \hyperref[csl:54]{(Lou et al. 2020)}. This study revealed an increased
ReHo in the left precentral gyrus and a decreased in the right
operculum. They also identified ReHo changes in some specific frequency
bands within the superior frontal gyrus, the superior parietal gyrus,
the anterior cingulate gyrus, the putamen, the superior temporal gyrus
and the operculum.
Using graph theory on resting-state fMRI, the study of Openneer et al
demonstrated that TS is related to dysfunction within the default mode
(for local efficiency and clustering coefficient) and that tic severity
is correlated with dysfunction within both the fronto-parietal and the
default mode networks without relation with ADHD comorbidity
\hyperref[csl:55]{(Openneer et al. 2020)}. This suggests an immature topological brain
organization specifically related to TS.
\subsubsection*{Pharmacological studies}
{\label{740561}}
A fascinating study on endocannabinoids was reported using CSF from 20
adults with TS and 19 controls~\hyperref[csl:56]{(Müller-Vahl et al. 2020)}.~The authors measured
anandamide (AEA), 2-arachidonoylglycerol (2-AG), palmitoyl ethanolamide
(PEA), and arachidonic acid (AA). The key results were that ``CSF AEA
(p\selectlanguage{english} =\selectlanguage{english} 0.0018), 2-AG (p\selectlanguage{english} =\selectlanguage{english} 0.0003), PEA (p\selectlanguage{english} =\selectlanguage{english} 0.02), and AA
(p\selectlanguage{english} \textless{}\selectlanguage{english} 0.0001) were significantly increased in TS compared with
controls,'' and that ``levels of 2-AG correlated with the severity of
comorbid ADHD (p\selectlanguage{english} \textless{}\selectlanguage{english} 0.01).'' The authors note these differences
could relate to compensation for chronic tics, or may be causative.
137 children with CTD were assessed at baseline, during a tic
exacerbation, and 2 months later \hyperref[csl:57]{(Addabbo et al. 2020)}.~Serum anti-D2R
antibodies were measured. 8\% had anti-D2R antibodies~during the
exacerbation, and 8\% of those with 2-month data at~2 months after the
exacerbation. The~\selectlanguage{greek}α\selectlanguage{english}D2R antibodies were significantly associated with
exacerbations, with or without correction for patient characteristics
including medication use. These antibodies may~possibly worsen tics via
antibody receptor blockade. Further research is needed to clarify the
causal role.~See also the commentary by \hyperref[csl:58]{(Conceição 2020)}.
\subsubsection*{Clinical and neuropsychological
studies}
{\label{389316}}
Impaired associative learning was shown in 46 children with TS compared
to 46 matched control children who performed the~Rutgers Acquired
Equivalence Test (face and fish test)~\hyperref[csl:59]{(Eördegh et al. 2020)}. This test
includes an acquisition phase (associating two visual stimuli based on
feedback~ of correct~\emph{vs.} incorrect), which depends on intact
basal ganglia function, and a test phase (retrieval of previous
association and generalization to predictable new stimuli), which
depends on the hippocampus and medial temporal lobe. The~TS group
performed worse on the acquisition phase (number of trials and
accuracy), regardless of comorbid ADHD, OCD, autism spectrum disorder or
medication status. However, they performed normally on~retrieval and
generalization. Compare two prior studies showing that people with TS
have abnormal probabilistic classification learning, which also involves
the dorsal striatum \hyperref[csl:60]{(Kéri et al. 2002}; \hyperref[csl:61]{Marsh et al. 2004)}.
Inhibitory control continues to be a matter of debate in TS. In this
topic, a first study explored reactive inhibitory control in adult
patients by using a stop-signal task~\hyperref[csl:62]{(Atkinson-Clement et al. 2020)}. Reactive
inhibition was not impaired in all TS patients but only in medicated
patients (essentially aripiprazole). In addition, impairment in this
group was underpinned by brain structures and functional connectivity of
the fronto-temporo-basal ganglia-cerebellar pathway.
A second study from the same group focused on another form of motor
impulsivity called ``waiting impulsivity'' defined as the difficulty to
withhold a specific action~~\hyperref[csl:63]{(Atkinson-Clement et al. 2020)}. The authors demonstrated
that this form of impulsivity is present in TS patients and correlates
with tics severity, but is normalised by medication (mainly
aripiprazole). In addition, waiting impulsivity in unmedicated TS
patients was related to abnormal gray matter intensity in deep limbic
structures, and with connectivity between cortical and cerebellar
regions.
A third and very interesting study compared automatic and volitional
inhibition in 19 adult patients with primary tic disorder in comparison
to 15 healthy controls~\hyperref[csl:64]{(Rawji et al. 2020)}. They used a conditional
stop-signal task associated with motor cortex TMS to assess reactive
volitional inhibition, and a masked priming task to assess proactive
automatic inhibition. This opposition is of particular interest since
volitional inhibition could be increased to prevent tics to reach the
threshold for expression, while automatic inhibition could prevent the
initial excitation of the striatal tic focus. The authors found that
volitional movement preparation, execution and inhibition are not
impaired in patients. Conversely, automatic inhibition was found as
impaired in patients which was also correlated to tic severity. ~
On the same theme of voluntary movements, Mainka et
al.~\hyperref[csl:65]{(Mainka et al. 2020)} published a follow-up study of a previous one on
mental chronometry~\hyperref[csl:66]{(Ganos et al. 2015)}. If they found no difference
between TS patients and healthy controls on the estimated time of their
own voluntary movements and the conscious intention to make a voluntary
movement, they identified a linear association between both these
variables and the disease duration. The longer the disease duration, the
lesser the performance were changed with the data of the first study.
For the authors, the chronic tics persistence at adulthood could be
associated with developmental impairment of internal premotor
processing. ~
To go further on the assessment of perception-action impairment in TS,
members of the same group published an interesting study
\hyperref[csl:67]{(Kleimaker et al. 2020)}. Based on the theory of Event
Coding~\hyperref[csl:68]{(Hommel et al. 2001}; \hyperref[csl:69]{Hommel 2009)}, a visual-motor event file task and EEG
recording, they found that perception-action binding was increased in
Tourette patients and partially correlated with tic frequency.
Interestingly, EEG results revealed that this process was not solely
related to motor and perceptual processes, but also to cognitive
processes (i.e., involving the inferior parietal cortex). Based on these
results, they conclude that the investigation of perception-action
binding in TS is more relevant than the assessment of only motor or
perception alone.
The association between real and perceived action in TS was also
assessed by using a finger-tapping synchronization task
\hyperref[csl:70]{(Graziola et al. 2020)}. Interestingly, the authors observed an impaired
temporal control in two opposite ways for TS and TS+ADHD patients. The
first were ``behind the beat'', the second were ``ahead of the beat''.
This confirmed that TS is related to an impairment of temporal motor
control.~
This year, two articles also assessed reward evaluation in TS. The first
one revealed that adolescents with TS present a higher delay discounting
specifically for large rewards \hyperref[csl:71]{(Vicario et al. 2020)}. In other words, if
they have the choice between a large immediate reward and a larger
delayed reward, TS patients are less likely to wait for the larger
option than healthy controls. This result is of importance and could
contribute to the debate on impulsivity from a more cognitive
standpoint. The second one used a reinforcement learning task with
various reward probabilities \hyperref[csl:72]{(Schüller et al. 2020)}. The authors showed
that TS patients had lower learning curves than healthy controls, but
also that reaction time of the healthy was influence by the reward
amount which was not the case for patients. In addition, EEG recording
revealed an attenuated P3a (positive fronto-central peaking) modulation
was found in TS, which was interpreted as an impaired coding of
attention allocation.
\subsection*{Treatment}
{\label{607471}}
\subsubsection*{Psychological
interventions}
{\label{813573}}
Behavior therapy (BT) is considered to be the first line treatment since
publication of the 2019 AAN guidelines, based on controlled randomized
trials. In a naturalistic setting (children and adolescents with chronic
tics, n=74) and over a 12 month follow-up period, it could be
demonstrated that~BT is and remains effective in 75\% of patients
analyzed, attesting not only to its efficacy but durability
\selectlanguage{ngerman}\hyperref[csl:73]{(Andrén et al. 2021)}.
Internet-based BT programs are investigated by multiple groups to make
BT available to a larger number of patients, rendering it thus
independent on the availability of trained practitioners and financial
considerations in countries where psychotherapy is not reimbursed by
social security. Rachamin et al. offer preliminary data on~
internet-based guided self-help comprehensive behavioral intervention
for tics (I-CBIT) in 25 youths (passive control group/waiting list,
n=16), and show this approach to be both effective and well received
over a 6 month period. Larger trials including an active control group
are necessary to confirm these first positive
results~\hyperref[csl:74]{(Rachamim et al. 2020)}.~
Another way to increase access to BT for tic treatment is group
training. The ``Tackle your Tics'' program is an intensive four day
course based on an enhanced version of ERP (exposure and response
prevention). First results in 13 youth offer promising results regarding
tic reduction and increased quality of life, with a two month follow-up
period. Larger controlled trials with longer follow-up periods are
awaited~awaited~\hyperref[csl:75]{(Heijerman-Holtgrefe et al. 2020)}.
Still another approach is to train parents as therapists. For that
purpose, an instructional video guide (on DVD) based on habit reversal
training was developed and applied (n=33), and compared to in-person
training (n=11) in children (mean age 10 years). Home-based,
parent-administered HRT was as efficacious for tic reduction as
traditional in-person training. However, the drop out rate in the former
group was close to 50\%, so that the authors advocate regular phone
contacts during the DVD treatment course, which squares with other
hybrid formats such at BipTic \hyperref[csl:76]{(Singer et al. 2020)}.
A very small (n=3) case series described an interesting new BT technique
based on attention training to suppress tics: to be followed
\hyperref[csl:77]{(Schaich et al. 2020)}.~
So far, BT is usually proposed for children above the age of ten. In
this very interesting proof of concept study, Bennett et al. test a CBIT
format (``CBIT-Jr.'') for children ages 5-8 (n=16) and show good
response (tic reduction) and acceptance. Moreover, they monitor these
improvements over a one year period and speculate that early BT might
alter the chronic course of tics: this is a very important subject and
should be investigated in larger, longitudinal cohorts
\hyperref[csl:78]{(Bennett et al. 2020)}.~
Remarkably, comprehensive behavior intervention for tics (CBIT) was
shown as also normalizing inhibitory control in a specific task of
perception-action bindings \hyperref[csl:79]{(Petruo et al. 2020)}.
\subsubsection*{Neurosurgery}
{\label{294711}}
An Italian center reports their experience with anterior GPi vs. Cm-Pf
DBS for TS~\hyperref[csl:80]{(Servello et al. 2020)}. Forty-one TS patients had DBS in
ventro-oralis / centromedian-parafascicular thalamus and 14 had DBS in
anteromedial GPi. The authors followed them for 4 years. YGTSS and
Y-BOCS improved in both groups (p\textless{}.001), but Y-BOCS improved
more in the GPi group. Hardware removal was limited to the thalamic DBS
group (13/41,~\emph{vs.} 0/14 in the GPi group).
The DBS registry (n=66 bilateral GPi, n=32 centromedian {[}Cm{]}
thalamus) has provided additional important
information~\hyperref[csl:81]{(Johnson et al. 2020)}.~Probabilistic tractography from
estimated volumes of tissue activated (VTAs) was used to identify
networks correlated with improvement in tics or OCD symptoms. Cleverly,
these networks were in turn used as seed regions for~``reverse''
tractography to identify local ``hot spots'' and ``cold spots.'' For GPi
targets, connectivity to limbic and associative networks, caudate,
thalamus and cerebellum predicted clinical improvement scores. The
anteromedial GPi showed higher connectivity to this network, and the
extent to which estimated VTA overlapped with this anteromedial region
correlated with tic improvement. For Cm targets, connectivity~to
sensorimotor and parietal-temporal-occipital networks, putamen and
cerebellum correlated with tic improvement. The anterior/lateral part of
the Cm region was more highly connected to this network.~For both sites,
connectivity to prefrontal, orbitofrontal and cingulate cortex
correlated with OCD improvement. These results suggest that structural
connections of focal stimulation sites to specific networks may lead to
clinical benefit. Interestingly, the identified networks may differ not
only by symptom but also based on the surgical target region.
A German study explained the effect of centromedian thalamic nucleus
deep brain stimulation by using probabilistic tractography in 7 TS
patients \hyperref[csl:82]{(Andrade et al. 2020)}. They highlighted that the tic reduction
following DBS was related to the degree of stimulation-dependent
connectivity between the centromedian thalamic nucleus and the
pre-supplementary motor area. Conversely, non-responders had more active
fibers that project into non-motor cortical areas.
\subsubsection*{Other treatments}
{\label{568802}}
A fascinating report from the University of Nottingham described~a
potential novel treatment for tics that uses the peripheral nervous
system to induce changes in primary sensorimotor
cortex~\hyperref[csl:83]{(Morera Maiquez et al. 2020)}.~The radical new idea arose from observations
associating movement inhibition with 8-14 Hz activity in motor cortex.
The authors first showed that rhythmic 12 Hz peripheral stimulation of
the median nerve evoked synchronous contralateral EEG activity over
primary sensorimotor cortex, whereas arrhythmic stimulation at the same
mean rate did not. As hypothesized, median nerve stimulation (MNS) at 12
Hz created small but statistically significant effects on initiation of
voluntary movements. Importantly, this stimulation did not meaningfully
impair concentration, suggesting that the effect did not operate through
simple distraction. Next they tested 10 Hz MNS in 19 TS patients, and
demonstrated using blinded video ratings a significant reduction in tic
number and severity during 1-minute stimulation epochs vs 1-minute
no-stimulation epochs. Videos accompanying the publication showed
dramatic benefit during MNS in some subjects.
\hyperref[csl:84]{(Sukhodolsky et al. 2020)} report intriguing results from a controlled,
crossover design, pilot study of real-time fMRI neurofeedback. Tics
improved more with real than sham feedback, the improvement was
clinically meaningful (3.8-point decline in YGTSS total tic score), and
the effect size was 0.59. Surprisingly, however, the two treatment
conditions did not differ in the putative mechanism of benefit, namely
control over SMA activity. An accompanying commentary is also useful
\hyperref[csl:85]{(Coffey 2020)}.
The role of the microbiome in the etiology and pathogenesis of various
CNS disorders has attracted widespread interest over the past decade,
with fecal transplantation being hailed as a potential treatment. Zhao
et al.~\hyperref[csl:86]{(Zhao et al. 2020)} report in an exploratory trial in children
with TS that this approach resulted in a significant tic decrease
(\textgreater{}25\% on the YGTSS-TTS) in four out of five subjects
during the 8 week trial period. However, there was no placebo group and
larger, randomized trials are warranted.~~
Physical exercise is advocated as positive for a plethora of somatic and
mental disorders these days, and TS is no exception. Jackson et al.
propose that aerobic exercise training (kick boxing) decreased tic
frequency in young people with TS (n=18, age 10-20 years), likely though
enhancement of cognitive control~\hyperref[csl:87]{(Jackson et al. 2020)}. Interestingly, tic
frequency reduction was less in a Tai Chi group, in which cognitive
control enhancement was not significantly altered compared to
controls.~Thus, the type of physical exercise is important, ``aerobic''
being the key word here~\hyperref[csl:87]{(Jackson et al. 2020)}. In the same vein, but on an
observational basis,~Pringsheim et al. report that in 110 children with
TS, less vigorous physical activity indeed correlated with tic severity.
This negative correlation could also be found for light exposure and
subjective sleep quality~\hyperref[csl:88]{(Pringsheim et al. 2021)}.~
Spanish researchers conducted an open trial of a gluten-free diet in 34
TS patients (mostly children) without celiac disease~\hyperref[csl:89]{(Rodrigo et al. 2018)}.
After a year, in the 29 patients who did not withdraw due to dietary
noncompliance, tics, OCD symptoms and quality of life were all improved
substantially compared to baseline. Prospective data on a dietary
intervention, as in this study, are greatly needed. However, this study
design cannot exclude improvement due to expectation effects or
regression to the mean, so a randomized, controlled trial is essential
before we can justify adding dietary restrictions to treatment
recommendations.
A survey of 90 respondents from 13 countries showed that online support
communities offer valuable informational and emotional support to those
living with tic disorders / TS and their families, especially in the
light of local face-to-face support that is often lacking. However, some
disadvantages also became apparent, such as~he suggestible nature of
tics and being reminded of the challenging nature of tic disorders.~
Also, some conflict arising within online communities were
noted~\hyperref[csl:90]{(Perkins et al. 2020)}.
Complementary and alternative medicine (CAM) blossoms in all of
medicine, and here too, TS is no exception. A survey of 110 patients
with TS showed that more than two thirds used one or more CAM therapies.
The most popular were: stress management, herbal medicine, homeopathy
and meditation. 93\% reported a decrease in tic frequency and 46\%
considered CAM more efficient than medication~\hyperref[csl:91]{(Patel et al. 2020)}.
Patients reported they often did not mention CAM treatments to their
treating physicians, placing the onus on clinicians to ask patients
specifically about them.~ These results also support the crucial need
for randomized, controlled trials of any intervention.
\section*{Conclusions}
{\label{563092}}
They are the same as last year (and likely for a while to come) but
worth reiterating, and consist of several simple but important
questions: Why do tics tend to start at ages 5--10? Why are they more
common in boys? Why do they tend to improve during sleep? Why do tics
usually improve in early adulthood? How accurately can we predict
outcome for an individual patient? Which patients need which treatments?
Is secondary prevention possible? Hopefully future studies will address
these and other important issues.
\section*{Competing interests}
{\label{742814}}
KJB participated in a clinical trial sponsored by Emalex Biosciences. AH
received consultancy fees from Noema Pharma.
\section*{Grant information}
{\label{472015}}
This work was supported in part by the U.S. National Institutes of
Health (NIH), grant R01 MH104030. The authors confirm that the funder
had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
\selectlanguage{english}
\FloatBarrier
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\end{document}