Abstract
This is the sixth yearly article in the Tourette Syndrome Research Highlights series, summarizing research from 2019 relevant to Tourette syndrome and other tic disorders. The highlights from 2020 is being drafted on the Authorea online authoring platform; readers are encouraged to add references or give feedback on our selections comments feature on page. After the calendar year ends, article is submitted as the annual update for the Tics collection F1000Research.
Introduction
This article is meant to disseminate recent scientific progress on Gilles de la Tourette Syndrome (TS).
Methods
We searched PubMed from time to time during 2019 using the search strategy “("Tic Disorders"[MeSH] OR Tourette NOT Tourette[AU]) AND 2019[PDAT] NOT 1950:2018[PDAT]”. On 16January 2020 this search
returned 211 citations. Colleagues also recommended articles, and we attended selected medical conferences. We selected material for this review subjectively, guided by our judgment of possible future impact on the field.
Results
Phenomenology and natural history
\citet{30661132} present a stimulating argument based on data that demonstrate a severity continuum between chronic tics and TS using a database regrouping 1018 subjects. They thus conclude that TS and chronic tics do not represent distinct diagnostic categories. Accordingly, they suggest the introduction of the the term "tic spectrum disorders" (in analogy to autism spectrum disorders) which might present the added benefit of decreased social stigma related to TS.
Martino and Hedderly provide an excellent review on the differences between tics and stereotypies, and their clinical management \citep*{30773283}
A video atlas of various vocalizations, with features distinguishing tics \citep{31651053}.
Epidemiology
Several good epidemiological studies and meta-analyses on the childhood prevalence of TS have been published over the past years, with most figures ranging between 0.5 to 0.8%. However, prevalence in adulthood remains unknown. Levine et al. analyzed three studies (published 1986, 2011 and 2016) involving 2,356,485 participants \citep{31220521}. Overall prevalence of TS in adulthood was estimated to be 118 cases of TS per million adults, that is 0.0118%. This appears very low, even factoring in remission in two thirds to three quarters of childhood cases during adulthood (which, in itself, is debatable). Clearly, more research is needed on this important topic, preferrably using current DSM-5 criteria.
Theory of evolutionary origins of imitative behavior and sympathetic emotions \citep*{30962461}.
Transient environmental effects on tic severity
Tic suppression
"Tic suppression in children with recent-onset tics predicts one-year tic outcome." \citep{31241402}
Sensory phenomena and premonitory urges
A hypothesis about sensorimotor causation of tics \citep{30890965}
Other
Association with metabolic and cardiovascular disorders \citep{30640363}
Contagious yawning is suppressed when a real human is in the room (but not seen) during virtual reality (VR) presentation of yawns, but not when images of people or of recording devices were present in the VR environment \citep{30670744}.
Etiology
Genetics
Polygenic risk scores yes, single genes no \citep{30818990}; TS-related genes expressed preferentially in DLPFC. Conclusions: "Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette’s syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette’s syndrome and other tic disorders in future diagnostic schemata. Tourette’s PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity."
ASH1L as a risk gene for TS \citep{31673123}
OCD and OC symptoms linked genetically to insulin signaling \citep{Widomska_2019}
De novo gene variants related to OCD overlap with genes implicated in TS \cite{31771860}
Maternal polycystic ovary syndrome (PCOS) is a risk for TS, ADHD and ASD \citep{30857571}
Environmental risk factors
Review of the PANDAS controversy by Don Gilbert (
link)
The EMTICS study (
https://cordis.europa.eu/project/id/278367/reporting?rcn=59137) was a large European multicenter trial investigating, among several subjects, the role of immunology in the etiology of tics, a long-discussed hypothesis in the context of PANS/PANDAS. A first paper on neuronal surface proteins on 188 patients with TS failed to confirm a link between pathogenic antibodies and causation of tics
(Baglioni et al. 2019). In line with these findings,
Baumgaertel et al. (2019) failed to detect autoantibodies in the CSF of 20 adult patients with TS. However, 20% of these patients had positive oligoclonal bands, an intriguing finding with no clear-cut explanation to date.
\citet{30833232a}, using the National Health Insurance Research Database of Taiwan, analyzed 2261 TS patients and 20349 non-TS controls for the risk of traumatic brain injury (TBI). During follow-up, there was a significantly increased risk for TBI in TS patients compared to controls. Classic comorbidities such as ADHD, OCD and depression increased the risk for TBI, whereas the regular use of antipsychotic medication decreased it. These findings have important therapeutic implications.
Pathophysiology
Animal models
Pathological studies
Electrophysiology
"Spatio-temporal structure of single neuron subthalamic activity in Tourette Syndrome explored during DBS procedures" \citep{Vissani_2019}.
Cued voluntary eye blinking studied by EEG in people with and without tics \citep{31382238}.
Neuroimaging studies
SERT binding increased in people with TS+OCD \citep{30700759}
Boys with anxiety disorders have altered WM in the uncinate fasciculus \citep{30654645}
The ENIGMA-OCD group was able to use their very large data set to show that individual subject "mega-analysis" is superior to a site-wise meta-analysis \citep{30670959}. This result will guide the nascent ENIGMA-TS group.
fcMRI study \citep{Nielsen2020}
"Alterations in basal ganglia-cerebello-thalamo-cortical connectivity and whole brain functional network topology in Tourette's syndrome" \citep{31518769a}
Pharmacological studies
"to assess reactive inhibitory control in adult TD patients with and without antipsychotic medication, and under emotional stimulation (visual images with positive, neutral and negative content)." DOI
10.1016/j.cortex.2019.12.007Clinical and neuropsychological studies
Young adults with TS showed reduced accuracy in the second step of a reaching task, consistent with a model in which forward updating of a model of the movement is abnormal \citep{30561518}.
"A superior ability to suppress fast inappropriate responses in children with Tourette syndrome is further improved by prospect of reward" \citep{31103639}.
Other
Treatment
Psychological interventions
In a large study of manualized CBT in children with OCD, anxious and depressive symptoms improved substantially and was not linked to improvements in OCD severity [
10.1016/j.psychres.2019.04.021 ]. This result is one more argument in favor of psychotherapy for obsessions and compulsions, which are common in people with tics. A consensus report argues strongly for early intervention in OCD
\citep{30773387}. Since early-onset OCD is associated with tics
\cite{21820387}, a similar argument could be made for early intervention in tic disorders, especially since effective behavioral treatments without side effects are available. Studies of whether early intervention changes the course of tic disorders are needed.
One of the most interesting possibilities in delivering CBT for tics has come from the development of internet-based platforms, making these approaches available for a large number of patients, even in remote areas. The BIP-TIC platform, developed in Sweden, allows to use either HRT, ERP or a mixture of both online with a possible intervention of a therapist by phone or email. A first pilot study on 23 patients has shown encouraging results in a rater-blind parallel group trial (including a 12 month follow up) \citep{30772854}. A large (n= +200) UK-based study using this platform, and focussing on en ERP-based g, called ORBIT, will commence shortly \citep{30610027}.
Another way to increase the number of patients to be reached by CBT is group therapy. A Danish study, using a combined HRT/ERP approach has demonstrated that it is equally effective in a group as in an individual setting with 27 patients per treatment arm \cite{Nissen2019}. This represents a promising and interesting way forward in CBT for tics.
Medication
Cannabis and cannabis-derived products are being considered for the treatment of tics – and a variety of other movement disorders – with great interest over the past years. Milosev et al. (2019) present results from a retrospective data analysis and an online survey on the use of cannabis-based medicine for tics and comorbidities in TS. Patients (n= 98 and 40) expressed a preference for medical cannabis (rich in THC) over dronabinol and nabiximols. However, results from large randomized trials are still awaited and will help guide therapeutic decisions. These will also depend, obviously, on the availability of different cannabis-based medications across countries.
Blocking tics by CBT or botulinum toxin has been hypothesized to interrupt the sensory-motor feedforward loop likely operating in TS, i.e. premonitory sensations triggering tics which then re-inforce premonitory sensations. Kimura et al. (2019) report on four patients who had undergone thalamic DBS for severe TS. In two, DBS could be completely withdrawn four and seven years after surgery, respectively, without re-increase in tics. This is intriguing and confirms unpublished reports from other centers, including our own (Paris). One major question in this regard is, of course, if the tics observed pre-op were purely organic of if some functional tics were also present. On this topic, Ganos et al. 2019 have published a landmark review which should be compulsory reading in the field.