This year brought widespread attention to social contagion as a possible cause of sudden-onset tic-like symptoms in adolescents. Such a phenomenon had been described previously, for instance ten years ago in a group of high school students in the Rochester, NY, area \cite{mechtler2012,24138153}, but in 2020, Müller-Vahl and German colleagues reported a rash of cases among patients who did not know each other in person, but had watched videos from the same social media personality and showed his same symptoms \citep{alexander2020}. A report from London \citep{33677431} reported a similar phenomenon and was picked up by numerous media outlets (a Google search 13 November 2021 for "functional tic-like behaviors, TikTok, social media" returned about 100 relevant results). Vera and colleagues carefully examined popular "Tourette" TikTok videos with unusual symptoms and described a number of features of these videos that are highly unusual for TS \citep{Vera_2021}. These features include aggression (in 19% of these videos), self-injurious behaviors (28%), coprophenomena (over half), long phrases (more than 3 words, 46%), throwing objects (22%), and very strong influence by the environment (over half). Senior clinicians viewing these videos rated them on a Likert scale of 1 (“All the tics are typical of TS”) to 5 (“None of the tics are typical of TS”). The median rating was 5 (interquartile range 4-5), meaning that almost none of these patients' presentations even slightly resembled TS to these clinicians. A group from Lübeck and Dresden directly compared demographic and clinical variables of 13 cases starting dramatically after social media exposure to 13 TS patients similar in age and sex \citep{34558735}. A number of features were seen only in the post-social-media patients (i.e., 100% specific), including abrupt symptom onset, first symptom complex, primarily slow and tonic movements, mostly trunk or extremities, a rapidly varying repertoire of symptoms, symptom deterioration in the presence of others, lack of spontaneous symptom fluctuations over the course of weeks to months, a symptom involving goal-directed movement (e.g. directed at another person), and dramatic context dependence. Symptoms continuing unabated during the examination was nearly as specific (13 of 13, vs. 1 of 10 with TS). Copropraxia was present in over half, as was echolalia, and symptom onset was significantly later (mean 15.3 years, vs. 5.2 years for TS). For all these reasons, most experts concluded that these presentations comprised a functional movement disorder rather than a variant expression of TS {can add additional refs here if desired}. The Tourette Association of America convened an international working group that provided a summary and recommendations for assessment and care \citep{robichaux-viehoeverForthcoming}; another helpful resource for patients is available at NeuroSymptoms.org \citep{tics2021}.
Pathophysiology
Animal models
Benzodiazepines and ethanol are among the well-known positive allosteric modulators (PAMs) of GABA-A receptors. A PAM highly selective for GABA-A receptors containing α6 subunits showed efficacy in the D1CT-7 transgenic mouse model of tics \citep{33525455}. Dopamine antagonists show similar effects but induce catalepsy, whereas this PAM did not. These results suggest strategies for future human studies including for treatment of tic disorders.
Previously, researchers had developed a model of persistent rodent grooming (potentially analogous to compulsions) when rodents consistently heard a tone before receiving a drop of water on the face, and linked this model to parvalbumin-containing GABAergic neurons in a prefrontal-striatal circuit. A group from Cold Spring Harbor and Johns Hopkins reported .... Inhibiting parvalbumin-containing GABAergic neurons in a prefrontal-striatal circuit previously implicated in excessive habit generation (persistent rodent grooming to a tone before a drop of water on the face) impairs feedforward inhibition (reviewed in TAA conference talk 2021-05-14). (See email from Kristen Delevich 2021-11-09 for more details.) See also \citep{32029441}.
Likely the most relevant and best established rodent models for tics have been developed by the group of Izhar Bar-Gad. In this paper, they provide a nice overview of their work so far \citep{Vinner2021}.
Pathological studies
Electrophysiology
In 2021, several review articles were published on electrophysiological studies to investigate the pathophysiology of tics and their implications for treatment. A review illustrates that electrophysiological studies are useful in understanding developmental brain dynamics in children and adolescents with Tourette syndrome and in understanding the clinical features of Tourette syndrome \cite{Rothenberger2021}. It is assumed that maturational delays and deficits in motor inhibition with cortico-spinal hyperexcitability in TS patients are well counteracted or compensated by spontaneous cognitive inhibition processes. This review discusses tics and premonitory urges as the processing of neural noise in information processing and adaptation to it, using EEG studies \cite{Münchau2021}. A systematic review highlights the advantages of noninvasive brain stimulation as a potential treatment for TS and discusses methodological (e.g., transcranial magnetic stimulation (TMS), transcranial direct current stimulation) and theoretical issues, including the possibility of reducing tics by applying multiple stimuli to the supplementary motor area (SMA) \cite{Dyke2021}. A double-blind, randomized, controlled trial performing transcranial magnetic stimulation (TMS) to the supplementary motor area and comparing the treatment effects of active repetitive TMS plus comprehensive behavioral intervention for tics (CBIT) versus sham repetitive TMS plus CBIT on a 1:1 basis in children with Tourette syndrome is being conducted \cite{Kahl2021}. Another systematic review discusses invasive direct brain stimulation, such as deep brain stimulation (DBS), for tics and obsessive-compulsive disorder, and shows that the effects of DBS on tics occur through different networks at different stimulation sites, and that connectivity analysis, not anatomical location, is sufficient to predict responses to OCD and TS \cite{Acevedo2021}.
Using EEG, researchers examined lateral readiness potentials, a measure of activation and preparation of responses occurring in motor cortical areas, and showed that action integration per se is normal in patients with TS, suggesting that TS is a disorder characterized by abnormalities outside the motor system \cite{Mielke2021}. A systematic review and meta-analysis investigating the electrophysiological correlates of performance monitoring in TS patients showed that error-related negativity significantly increased amplitude in TS participants \cite{Bellato2021}. However, this was based on only five studies and there was a high degree of heterogeneity between studies.
An EEG study of TS patients and controls examined movement-related EEG (i.e., mu- and beta-band oscillations) immediately before voluntary movements and tics were performed \cite{Morera2021}. The results showed that mu and beta oscillations were not reliably observed before the tic. They concluded it reflected that the generation of tics in TS involved a greater network of brain regions, including the insular cortex, cingulate cortex, basal ganglia, and cerebellum. In the same study, they showed that beta-band desynchronization occurred when TS patients initiated voluntary movements, but no desynchronization of mu-band oscillations was observed during the execution of voluntary movements in TS patients, in contrast to healthy controls. The authors interpreted the result as a physiological impairment of inhibition in TS, thereby contributing to an inability to inhibit neuronal populations potentially competing with the motor preparation process.
A patient was treated for major depressive disorder with bilateral ventral internal capsule and ventral striatum DBS and developed dose-dependent (voltage-dependent) coprolalia and limb movements, along with changes in affect, mood and memory \citep{33568978}. Inpatient observation supported the conclusion that these symptoms were most likely caused by the focal electrical stimulation. Although a single case, this report adds to previous data implicating primarily subcortical nuclei in secondary tic disorders.
Dual-site TMS and diffusion tensor imaging showed loss of normal prefrontal (pre-SMA) inhibition of motor cortex in 12 children with TS/CTD compared to 14 control participants \citep{33462641}. The decreased inhibition correlated to impairment of tic inhibition. Increased fractional anisotropy was also observed in several white matter pathways in TS/CTD. These results support similar previous findings in adults with TS and support a plausible pathophysiological mechanism relevant to tic persistence.
Two articles
here from early 2021 (Marceglia et al; Rothenberger et al)
Neuroimaging studies
In 2021, two VBM meta-analyses were published \cite{Wen2021,Wan2021}. If their objectives were the same (i.e., comparing TS patients to HC), they used different approaches and found some identical and some different results. The first \cite{Wan2021} selected 10 studies and used a voxel-wise meta-analysis called seed-based d mapping. The second \cite{Wen2021} selected 6 studies and used the more classical Activation Likelihood Estimation method (ALE). They both reported a decreased gray matter signal in the thalamus and the putamen and an increased in the postcentral gyrus. Surprisingly, their other results were not shared and are therefore to be considered as less strong: an increased gray matter signal in the cerebellum (vermis III), in limbic areas (striatum, insula and hypothalamus) and in sensorimotor regions (pre- and post-central gyri); a decreased gray matter signal in frontal (inferior and medial parts and rolandic operculum), temporal (superior temporal gyrus) and parietal cortices (supramarginal gyrus) as well as cingulate gyrus (anterior and posterior parts).