Electrophysiological studies were discussed as a possible therapeutic modality for tic disorders. Transcranial magnetic stimulation (TMS) for tics has been discussed in several reviews. Repetitive TMS has shown to improve tic symptoms and tic comorbidities, and its safety has been confirmed \cite{Bejenaru2022,Yu2022}. Other review articles have discussed not only on TMS but also on other electrophysiological modalities such as transcranial direct current stimulation (tDCS), peripheral nerve stimulation, and cranial electrotherapeutic stimulation (CES) \cite{Frey2022}. In contrast to repetitive TMS, tDCS, which stimulates by applying a constant low current to electrodes attached directly to the scalp, is inexpensive, portable, and easy to implement. To date, results have been mixed and inconclusive as many studies have been open-label designs. Vagus nerve stimulation (VNS) treatment has also been reported to improve tic symptoms, but it is still unknown how VNS affects tic symptoms. Stimulation of peripheral nerves (i.e., median nerve) with 12 Hz rhythmic pulses synchronized with mu-band oscillations in the brain has been reported to significantly reduce the frequency and severity of tics. CES is a small, portable device that stimulates the brain with a weak electric current and is being studied for its effectiveness in treating tic disorders.
Neuroimaging studies
One of the most significant publications on neuroimaging is probably the work done by Ganos et al. \cite{Ganos2022}, even if not directly focused on Tourette Syndrome. They used a seducing methodological approach which combined: (i) a comparison of brain lesions which induced tics (n=22) to control brain lesions which did not induce tics (n=717); (ii) they built a functional lesion network using healthy subjects’ fMRI (n=1000) and using the lesion location they found in the first step as seed; (iii) they assessed the utility of this lesion network to predict tics decrease after thalamic deep brain stimulation surgery on patients with Tourette Syndrome (n=30). Altogether, they highlighted a brain network related to tic-inducing lesions (insula, cingulate cortex, striatum, globus pallidus internus, thalamus and cerebellum), and a site in particular which is specific to tic: the putamen. Last, this network is a significant predictor of tics improvement after DBS.
Still on the topic of thalamic DBS, Baldermann et al. \cite{Baldermann_2022} used the data of 15 TS patients. They showed that tic reduction was related to (i) a positive relation was observed for the functional connectivity between the activated tissue by DBS and the sensorimotor cortex, the bilateral insula and the inferior frontal cortex, and (ii) a negative relation was described between the activated tissue and the cerebellum, the temporal and the orbitofrontal cortex, as well as with the ventral striatum.
Another study focused on subthalamic nucleus DBS for TS patients \cite{Dai_2022}. If they found a significant tics severity decrease (63% at 6 months and 59% at 1 year), they also identified that STN-DBS will improve tics severity by modulating a functional network which includes most of the motor basal ganglia (thalamus, pallidum, substantia nigra pars reticula, putamen), the insula and the anterior cingulate cortex.
From a purely pathophysiological viewpoint, three publications used MRI to identify abnormalities in TS. The first one \cite{Bharti_2022} highlighted that pure TS, as well as TS associated with OCD (both drug-naïve), were underpinned by an increased white matter fractional anisotropy in the corticospinal tract, the anterior thalamic radiations, the inferior longitudinal fasciculus and the corpus callosum, all correlated with tic severity. The second \cite{Liao_2022}, also focused on drug-naïve TS children, assessed topological brain alterations. If they found some networks metrics as abnormal at the global level (i.e., increased global efficiency, decreased path length), they also showed some nodal changes, especially in the cortico-striato-thalamo-cortical circuit (i.e., supplementary motor area, caudate nucleus, thalamus, superior parietal gyrus, posterior cingulate cortex). This study is especially relevant since the authors used brain metrics which are rarely investigated. The third study focused on gyral abnormalities \cite{McCann_2022}. They identified that the youngest TS patients (children) had an increased surface curvature in the frontal cortex (opercular and triangular parts of the inferior frontal cortex), while the oldest (adolescents) had an increased grey matter volume in the cerebellum, the precentral cortex and the primary motor cortex.
Another interesting work was published last year, using different statistical models to classify BOLD rs-fMRI of TS patients and healthy controls \cite{Xin_2022}. The model which achieved the highest accuracy (multivariate non-linear model, 94% of accuracy, 96% of sensitivity and 92% of specificity) was especially based on changes observed in the frontal cortex (superior, medial and middle frontal gyrus, supplementary motor area, pre- and postcentral cortex), basal ganglia (putamen, thalamus and caudate nucleus) and the cerebellum. In the future, this kind of work could lead to the build some specific tools to contribute to the diagnosis of TS.
From a more cognitive viewpoint, three studies linked specific TS symptoms to brain alterations. The first one investigated the relation between the structural connectivity of several basal ganglia (caudate nucleus, putamen, nucleus accumbens, subthalamic nucleus and the medial subthalamic region) and the cortex with anxiety and impulsivity in TS \cite{Temiz_2022}. They found a hyperconnectivity in TS patients between the left medial subthalamic region and the insula, entorhinal and temporal cortex. Moreover, the connectivity between the subthalamic nucleus and the left insula was shown as positively related to impulsivity and anxiety scores respectively measured with BIS-11 and the STAI. The second study focused on the role of GABA as related to the urges to tics through several measures of cortical inhibition obtained with TMS \cite{Larsh_2022}. They found that severe urges were negatively correlated to cortical excitability and long-interval cortical inhibition obtained in the primary motor cortex. However, they also found that more severe tics were positively correlated with both of these measures. Last, they found that the right supplementary motor area GABA (cortical excitability and long-interval cortical inhibition) was change in TS patients compared to healthy controls. Altogether, they concluded that changes in the primary motor cortex were modulated by GABA within the supplementary motor area and could reflect compensatory mechanisms. The third study focused on the error-related negativity obtained with MEG \cite{Metzlaff_2022}. This measure is known to reflect processes of performance monitoring, to be increased during error processing and conflicting response, and to be related to the dopaminergic system and the prefrontal cortex activity. Based on a small sample of adults’ patients without any medication nor comorbidities (n=8) performing a Go-NoGo task, the authors showed a significant interaction between groups (TS vs. healthy controls) and response (correct vs. error). The authors explained this difference by suggesting that TS patients processed all their responses as erroneous, which means that TS patients had an altered performance monitoring.
Lastly, the study by Morand-Beaulieu et al \cite{Morand_Beaulieu_2022} tried to determine if Comprehensive Behavioral Intervention effects to reduce tics severity are underpinned by EEG biomarkers. If they observed that this treatment successfully decreased tics severity, they failed to identify EEG biomarkers related to motor inhibition.