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
This article has been submitted to F1000Research. Please suggest articles from 2021 here. Feel free to suggest your own work as well as others'. Abstract
We present here research from 2020 relevant to Tourette syndrome (TS). The authors briefly summarize a few reports they consider most important or interesting.
Introduction
This article is meant to disseminate recent scientific progress on TS.
Methods
We searched PubMed during 2020 using the search strategy
("Tic Disorders"[MeSH] OR Tourette NOT Tourette[AU]) AND 2020[PDAT] NOT 1950:2019[PDAT]. On 15 Feb 2021 this search
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.
Results
Phenomenology and natural history
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 \citep{33776814}. 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 \citep{alexander2020}.
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. \citep{Cen2020}.
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 \citep{Robertson2020}. 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 \citep{Conte2020}. Similar observations were made by two further groups \citep{Graziola2020}\citep{Mataix-Cols2020}.
Epidemiology
Another analysis of the Swedish population registry revealed significantly more substance abuse and consequences—including substance-related death—in people with TS \citep{33229038}. 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 \citep{Mataix-Cols2021}. 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 \citep*{33188819}.
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 \citep{Rodin2021}.
Sensory phenomena and premonitory urges
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 \citep{32719621}
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 \citep{33173296}. By the same group, a comprehensive review on this topic with an accent on pathophysiology of sensory processing dysfunction in TS and associated disorders \citep*{Isaacs2020} .
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 \citep{Baumung2021}. 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 \citep{Openneer2020}.
Other
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 \citep{Hagstrøm2021}.
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 \citep{Conte2020a}. 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 \citep{Müller-Vahl2019}.
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 \citep{Benaroya-Milshtein2020}.
Two up-to-date and complete review of sleep disorders in TS appeared, covering both adults and children \citep{Jiménez-Jiménez2020}\citep{Hibberd2020}. Importantly, self-injurious behavior in TS was comprehensively reviewed by Stafford and Cavanna \citep*{32205150}.
Openneer and colleagues studied a cognitive control task in children with TS, ADHD, neither or both \citep{31901563}. 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 \citep{Kurvits_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 \citep{32443587}. 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.
Etiology
Genetics
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
CLCN2 (G161S), which was enriched in a TS cohort
\citep{Yuan2020}. Loss-of-function variants in
CLCN2, encoding the CLC-2 chloride channel, cause a leukoencephalopathy with ataxia, a recessive monogenic disorder
\citep{Depienne2013}. 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
CELSR3 in one proband
\citep{Zhao2020a}.
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
\citep{Wang2018}\citep{Willsey2017a}. A review by
Zhang and colleagues highlighted the possible role of variants in
ASH1L in the etiology of psychiatric disorders including TS, autism spectrum disorders and intellectual disability
\citep{Zhang2021}.
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
\citep{Krumm2015}. A single study making use of Array CGH identified a 260-kb duplication on chromosome Xq28 comprising two genes (
VAMP7 et
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
CNR1 (cannabinoid receptor 1),
LHX6, IMMP2L and
AADAC with TS
\citep{Szejko2020} \citep{Pagliaroli2020}. These association studies were performed on case-control populations limited in size and need further replication. Furthermore, a study showed that deletions altering
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
\citep{Bjerregaard2020}. 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
\citep{Wendt2021}.
Environmental risk factors
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 \citep{Martino2020}.
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%) \citep{31564049}. 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 \citep{9163399}.
Pathophysiology
Animal models
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 \citep{Recanatesi_2020,Recanatesi_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.
Electrophysiology
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 \citep{Cagle_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 \citep{Naro_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.