Etiology

Genetics and epigenetics

In 2023 three studies analyzed rare variants in TS. First, Saia and colleagues performed Array-CGH analysis of 93 phenotypically well-characterized TS cases to explore if the presence of pathogenic copy number variants (CNVs) was related with frequent clinical features. They investigated incidence of dysmorphic features, epilepsy, brain magnetic resonance imaging (MRI) anomalies, intellectual disability, and severity of symptoms in children with TS. They classified the CNVs as potentially causative variants (PC-CNVs) if they were reported to be associated with TS in the OMIM database, and as non-causative CNVs (NC-CNVs) if there was no previous association with TS reported or if they were of unknown significance. They performed statistical analyses to compare children with PC-CNVs, NC-CNVs and without CNVs (W-CNVs), and detected significant differences among the three groups for the occurrence of epilepsy or isolated EEG anomalies, brain MRI anomalies, intellectual disability and IQ \citep{Saia2023}.
Another study focusing on rare variants was performed by Fincha and colleagues. They performed a co-segregation analysis on 17 multiplex families including 80 TS or tic disorders patients and 44 healthy members. They prioritized 37 rare and possibly pathogenic variants shared by the cases within a family, and three ultra rare variants in two families. These variants are located in multiple genes and the majority of them on introns \citep{Fichna2023}.
Tsetsos and colleagues performed the largest Tourette Syndrome GWAS meta-analysis to date with a total of 6,133 TS cases and 13,565 controls, including a novel dataset. The increased sample size provided power to detect a novel genome-wide significant locus on chromosome 5q15, upstream of the NR2F1 gene. This locus was also supported by analyses combining eQTL, Hi-C and GWAS data. NR2F1 is a nuclear receptor that is a regulator of transcription. Additional analyses exploring the association of TS polygenic risk score with brain volume data revealed statistically significant associations with right and left thalamus volumes and right putamen volume \citep{Tsetsos2023}.
Jain and colleagues \citep{Jain2023} used TS GWAS summary statistics from Tsetsos and colleagues \citep{Tsetsos2023} to calculate the TS Polygenic Risk Score (PRS) on individuals in the UK Biobank and then performed a Phenome Wide Association Study (PheWAS) to assess the association of TS genetic risk with a wide range of phenotypes (n=2242). They identified significant associations with 57 traits including depression, anxiety disorder, respiratory conditions, type 2 diabetes and heart palpitations. They also performed cross-disorder comparisons of the PheWAS results with OCD, ASD, and ADHD. The study identified shared associations with multiple health and behavioral phenotypes. TS had similar direction of effects for almost all phenotypes with ASD and ADHD, but OCD had an opposite direction of effect compared to TS (for all phenotypes except mental health traits). Then, they performed sex-specific PheWAS for TS, and they found heart palpitations and type 2 diabetes to be significantly associated with TS risk in males but not in females, while diseases of the respiratory system were associated with TS risk in females but not in males. 
 Wang and colleagues explored the rare maternally-inherited variants on X chromosome in simplex autism families extending their findings also to TS. First, they identified risk-enriched regions (RERs) using microarray data, and then they used whole-exome sequencing data to explore the rare maternally-inherited damaging variants in autism followed by transmission disequilibrium test which pointed to novel autism risk gene, MAGEC3. They applied the same framework to TS and ADHD male probands, and they observed that both traits were enriched for rare damaging variants in RERs, with similar effect sizes to autism. Finally, they estimated that 27.54% of the rare damaging variants carry risk for TS, with similar percentages for the other two traits \citep{Wang2023}.
Hughes and colleagues used genetic data and measures of psychopathology from Adolescent Brain Cognitive Development (ABCD) and Generation R, as replication, cohorts to explore the relationships of eight psychiatric disorders and cross-disorder Polygenic Scores (PGSs) to dimensional psychopathology in mid-childhood. They observed that the latent neurodevelopmental (NDV) factor PGS, which included loadings from ADHD, autism spectrum disorder, major depressive disorder, and TS, explained more variance across the spectrum of psychopathology than any other disorder-specific or cross-disorder PGS. They also performed gene-based association tests to define the NDV enriched genes (n=68) that were then included in downstream analyses to explore the pathways affecting the risk for childhood psychopathology. The gene ontology (GO) enrichment analysis of these genes did not return any significant results after FDR correction, however tissue expression showed that they were more strongly expressed in the cerebellum followed by cerebral cortical and subcortical regions. Gene expression analysis within the cerebellum from postmortem fetal and postnatal brain tissue, showed that the NDV genes (N = 68) were expressed significantly more strongly prenatally \citep{Hughes2023}.
Jiang and colleagues \citep{Jiang2023} performed a two-sample Mendelian Randomization study to explore the causal relationships between plasma phosphodiesterases and psychiatric disorders, including TS. In the analysis for TS they used GWAS summary statistics from Yu and colleagues \citep{Yu2019}, and they observed a positive association of PDE5A with TS, while PDE2A was negatively associated with TS, however for both cases the associations were almost at nominal level.
Mahjani and colleagues utilized the Swedish Medical Birth Register to explore the direct additive genetic effect, genetic maternal effect and environmental maternal effect on CTD liability. They identified 6227 individuals with CTD diagnosis and by applying generalized linear mixed models they observed 60.7% direct additive genetic effect, 4.8% genetic maternal effect and 0.5% environmental maternal effect \citep{Mahjani2023}.

Pathophysiology

Neurophysiology

In 2023, a few studies used EEG to assess brain connectivity patterns in individuals with TS. Jurgiel and colleagues investigated the additive and interactive effects of TS and ADHD on effective connectivity in children \citep{Jurgiel_2023}. They reported additive effects of aberrant effective connectivity in TS and ADHD spanning several frequency bands. Aberrant effective connectivity was mostly found in children with ADHD, who showed reduced effective connectivity across several posterior and occipital-frontal connections. TS was associated with increased connectivity from the left postcentral to the right precuneus and reduced connectivity from the left occipital cortex to the right precuneus. Another EEG study, which was conducted in adults, assessed functional connectivity within and across nodes of the default mode network \citep{Yang_2023}. They found increased beta-band connectivity between the left and right posterior cingulate/retrosplenial cortices, relative to controls. Also, using graph theoretical metrics, they found enhanced gamma-band degree centrality in the left temporal lobe, which was significantly correlated with increased tic severity. 
Two EEG studies have investigated proactive control and binding processes in TS \citep{Wehmeyer_2023,Wendiggensen_2023}. In the first study, EEG markers of proactive control and binding were recorded during a cued task switching paradigm in adults with TS \citep{Wehmeyer_2023}. After temporal decomposition, they found an absence of N2 modulation but increased P3 for repeated responses on task switch trials in the C-cluster, which includes intermediate processes between stimulus and response. In the second study, a S1-S2 paradigm was used to assess binding processes in adolescents and adults with TS \citep{Wendiggensen_2023}. Their analyses, which focused on the theta frequency band, revealed that action file binding effects in the control group relied on the superior parietal regions cortex and the precuneus, whereas the superior frontal gyrus was involved in individuals with TS. Of note, both studies support the idea that integration of action in individuals with TS involves different neurophysiological processes, relative to controls.
To test whether altered social behaviors in TS reflected an overactive mirror neuron system, Weiblen and colleagues investigated mu suppression during an empathy for pain task in adults with TS \citep{Weiblen_2023}. Mu suppression is thought to reflect empathic abilities and could serve as a marker of mirror neuron system function. During the experimental task, participants viewed pictures of hand and feet in neutral or painful situations. Study results revealed that adults with TS showed reduced pain-related mu suppression relative to controls, suggesting altered processing of others’ emotional states.
Triggiani and colleagues assessed the sense of volition and the neural antecedents of tics and voluntary movements using a Libet's clock paradigm \citep{Triggiani_2023}. They asked adults with TS and controls to take note of the time they had the conscious intention to move and the time when they felt the initiation of a voluntary movement. However, groups did not differ on those measures. Those with TS were also asked to judge the timing of the intention and the initiation of tics, but those did not differ from the timing of voluntary movements. While most adults with TS showed a Bereitschaftspotential prior to tics, beta desynchronization was absent in a majority of individuals, suggesting dissociation between both processes. Furthermore, as commented by Gunduz and Ganos, the absence of beta desynchronization prior to tics could possibly help in distinguishing primary tics from functional tic-like behaviors \citep*{Gunduz_2023}.
Other electrophysiological studies aimed to investigate motor cortical inhibition using transcranial magnetic stimulation. Consistent with previous findings \citep[see][]{Larsh_2022a}, Batschelett and colleagues found no difference between children with TS and controls in terms of motor cortex short-interval cortical inhibition \citep{Batschelett_2023a}. However, short-interval cortical inhibition was significantly associated with increased tic severity. Schmidgen and colleagues used transcranial magnetic stimulation to evoke the N100 event-related potential, a marker of motor cortical inhibition thought to reflect GABAB receptors functioning \citep{Schmidgen_2023}. They found reduced modulation of N100 by external (different stimulation intensities) and internal (different motor states: movement preparation and execution) modulation in children with TS. These results suggest altered modulation of motor cortical inhibition in TS, which would be related to GABAB processes.

Neuroimaging studies

One of the most noteworthy neuroimaging studies of the last year was conducted by Zouki and colleagues \citep{Zouki_2023}. Similar to a study published the preceding year \citep{Ganos_2022}, they combined both lesion-network mapping (derived from cases associated with tic-inducing lesions) and resting-state functional networks obtained in patients with TS. While the precise anatomical localization of the lesions did not reveal a singular site related to tics, the network-based analysis highlighted a neural network implicating the posterior putamen, the caudate nucleus, the globus pallidus externus, and the precuneus. As a second level analysis, this network was found to be functionally disconnected in TS patients with a specific cluster identified in the right frontal white matter and cingulate gyrus. As highlighted in the accompanying scientific commentary \citep{Ganos_2023}, the robustness of these findings underscores their potential translation into clinical practice, offering promising avenues for the development of targeted therapeutic interventions.