Using graph theory on resting-state fMRI, the study of Openneer et al demonstrated that TS is related to dysfunction within the default mode (for local efficiency and clustering coefficient) and that tic severity is correlated with dysfunction within both the fronto-parietal and the default mode networks without relation with ADHD comorbidity \citep{Openneer_2020}. This suggests an immature topological brain organization specifically related to TS.

Pharmacological studies

A fascinating study on endocannabinoids was reported using CSF from 20 adults with TS and 19 controls \citep{32272483}. The authors measured anandamide (AEA), 2-arachidonoylglycerol (2-AG), palmitoyl ethanolamide (PEA), and arachidonic acid (AA). The key results were that “CSF AEA (p = 0.0018), 2-AG (p = 0.0003), PEA (p = 0.02), and AA (p < 0.0001) were significantly increased in TS compared with controls,” and that “levels of 2-AG correlated with the severity of comorbid ADHD (p < 0.01).” The authors note these differences could relate to compensation for chronic tics, or may be causative.
137 children with CTD were assessed at baseline, during a tic exacerbation, and 2 months later \citep{32644201}. Serum anti-D2R antibodies were measured. 8% had anti-D2R antibodies during the exacerbation, and 8% of those with 2-month data at 2 months after the exacerbation. The αD2R antibodies were significantly associated with exacerbations, with or without correction for patient characteristics including medication use. These antibodies may possibly worsen tics via antibody receptor blockade. Further research is needed to clarify the causal role. See also the commentary by \citep{32662071}.

Clinical and neuropsychological studies

Impaired associative learning was shown in 46 children with TS compared to 46 matched control children who performed the Rutgers Acquired Equivalence Test (face and fish test) \citep{32544176}. This test includes an acquisition phase (associating two visual stimuli based on feedback  of correct vs. incorrect), which depends on intact basal ganglia function, and a test phase (retrieval of previous association and generalization to predictable new stimuli), which depends on the hippocampus and medial temporal lobe. The TS group performed worse on the acquisition phase (number of trials and accuracy), regardless of comorbid ADHD, OCD, autism spectrum disorder or medication status. However, they performed normally on retrieval and generalization. Compare two prior studies showing that people with TS have abnormal probabilistic classification learning, which also involves the dorsal striatum \citep{11931939a,15583117a}.
Inhibitory control continues to be a matter of debate in TS. In this topic, a first study explored reactive inhibitory control in adult patients by using a stop-signal task \citep{Atkinson_Clement_2020a}. Reactive inhibition was not impaired in all TS patients but only in medicated patients (essentially aripiprazole). In addition, impairment in this group was underpinned by brain structures and functional connectivity of the fronto-temporo-basal ganglia-cerebellar pathway.
A second study from the same group focused on another form of motor impulsivity called "waiting impulsivity" defined as the difficulty to withhold a specific action  \citep{Atkinson_Clement_2020b}. The authors demonstrated that this form of impulsivity is present in TS patients and correlates with tics severity, but is normalised by medication (mainly aripiprazole). In addition, waiting impulsivity in unmedicated TS patients was related to abnormal gray matter intensity in deep limbic structures, and with connectivity between cortical and cerebellar regions.
A third and very interesting study compared automatic and volitional inhibition in 19 adult patients with primary tic disorder in comparison to 15 healthy controls \citep{Rawji_2020}. They used a conditional stop-signal task associated with motor cortex TMS to assess reactive volitional inhibition, and a masked priming task to assess proactive automatic inhibition. This opposition is of particular interest since volitional inhibition could be increased to prevent tics to reach the threshold for expression, while automatic inhibition could prevent the initial excitation of the striatal tic focus. The authors found that volitional movement preparation, execution and inhibition are not impaired in patients. Conversely, automatic inhibition was found as impaired in patients which was also correlated to tic severity.  
On the same theme of voluntary movements, Mainka et al. \citep{Mainka_2020} published a follow-up study of a previous one on mental chronometry \citep{Ganos_2015}. If they found no difference between TS patients and healthy controls on the estimated time of their own voluntary movements and the conscious intention to make a voluntary movement, they identified a linear association between both these variables and the disease duration. The longer the disease duration, the lesser the performance were changed with the data of the first study. For the authors, the chronic tics persistence at adulthood could be associated with developmental impairment of internal premotor processing.  
To go further on the assessment of perception-action impairment in TS, members of the same group published an interesting study \citep{Kleimaker_2020}. Based on the theory of Event Coding \citep{Hommel_2001,Hommel_2009}, a visual-motor event file task and EEG recording, they found that perception-action binding was increased in Tourette patients and partially correlated with tic frequency. Interestingly, EEG results revealed that this process was not solely related to motor and perceptual processes, but also to cognitive processes (i.e., involving the inferior parietal cortex). Based on these results, they conclude that the investigation of perception-action binding in TS is more relevant than the assessment of only motor or perception alone.
The association between real and perceived action in TS was also assessed by using a finger-tapping synchronization task \citep{Graziola_2020}. Interestingly, the authors observed an impaired temporal control in two opposite ways for TS and TS+ADHD patients. The first were “behind the beat”, the second were “ahead of the beat”. This confirmed that TS is related to an impairment of temporal motor control. 
This year, two articles also assessed reward evaluation in TS. The first one revealed that adolescents with TS present a higher delay discounting specifically for large rewards \citep{Vicario_2020}. In other words, if they have the choice between a large immediate reward and a larger delayed reward, TS patients are less likely to wait for the larger option than healthy controls. This result is of importance and could contribute to the debate on impulsivity from a more cognitive standpoint. The second one used a reinforcement learning task with various reward probabilities \citep{Sch_ller_2020}. The authors showed that TS patients had lower learning curves than healthy controls, but also that reaction time of the healthy was influence by the reward amount which was not the case for patients. In addition, EEG recording revealed an attenuated P3a (positive fronto-central peaking) modulation was found in TS, which was interpreted as an impaired coding of attention allocation.

Treatment

Psychological interventions

Behavior therapy (BT) is considered to be the first line treatment since publication of the 2019 AAN guidelines, based on controlled randomized trials. In a naturalistic setting (children and adolescents with chronic tics, n=74) and over a 12 month follow-up period, it could be demonstrated that BT is and remains effective in 75% of patients analyzed, attesting not only to its efficacy but durability \citep{Andrén2021}.
Internet-based BT programs are investigated by multiple groups to make BT available to a larger number of patients, rendering it thus independent on the availability of trained practitioners and financial considerations in countries where psychotherapy is not reimbursed by social security. Rachamin et al. offer preliminary data on  internet-based guided self-help comprehensive behavioral intervention for tics (I-CBIT) in 25 youths (passive control group/waiting list, n=16), and show this approach to be both effective and well received over a 6 month period. Larger trials including an active control group are necessary to confirm these first positive results \citep{Rachamim2020}
Another way to increase access to BT for tic treatment is group training. The "Tackle your Tics" program is an intensive four day course based on an enhanced version of ERP (exposure and response prevention). First results in 13 youth offer promising results regarding tic reduction and increased quality of life, with a two month follow-up period. Larger controlled trials with longer follow-up periods are awaited awaited \citep{RN10144a}.
Still another approach is to train parents as therapists. For that purpose, an instructional video guide (on DVD) based on habit reversal training was developed and applied (n=33), and compared to in-person training (n=11) in children (mean age 10 years). Home-based, parent-administered HRT was as efficacious for tic reduction as traditional in-person training. However, the drop out rate in the former group was close to 50%, so that the authors advocate regular phone contacts during the DVD treatment course, which squares with other hybrid formats such at BipTic \citep{Singer2020}.
A very small (n=3) case series described an interesting new BT technique based on attention training to suppress tics: to be followed \citep{Schaich2020}
So far, BT is usually proposed for children above the age of ten. In this very interesting proof of concept study, Bennett et al. test a CBIT format ("CBIT-Jr.") for children ages 5-8 (n=16) and show good response (tic reduction) and acceptance. Moreover, they monitor these improvements over a one year period and speculate that early BT might alter the chronic course of tics: this is a very important subject and should be investigated in larger, longitudinal cohorts \citep{Bennett2020}
Remarkably, comprehensive behavior intervention for tics (CBIT) was shown as also normalizing inhibitory control in a specific task of perception-action bindings \citep{Petruo_2020}.

Neurosurgery

An Italian center reports their experience with anterior GPi vs. Cm-Pf DBS for TS \citep{32429219}. Forty-one TS patients had DBS in ventro-oralis / centromedian-parafascicular thalamus and 14 had DBS in anteromedial GPi. The authors followed them for 4 years. YGTSS and Y-BOCS improved in both groups (p<.001), but Y-BOCS improved more in the GPi group. Hardware removal was limited to the thalamic DBS group (13/41, vs. 0/14 in the GPi group).
The DBS registry (n=66 bilateral GPi, n=32 centromedian [Cm] thalamus) has provided additional important information \citep{32653920}. Probabilistic tractography from estimated volumes of tissue activated (VTAs) was used to identify networks correlated with improvement in tics or OCD symptoms. Cleverly, these networks were in turn used as seed regions for “reverse” tractography to identify local "hot spots" and "cold spots." For GPi targets, connectivity to limbic and associative networks, caudate, thalamus and cerebellum predicted clinical improvement scores. The anteromedial GPi showed higher connectivity to this network, and the extent to which estimated VTA overlapped with this anteromedial region correlated with tic improvement. For Cm targets, connectivity to sensorimotor and parietal-temporal-occipital networks, putamen and cerebellum correlated with tic improvement. The anterior/lateral part of the Cm region was more highly connected to this network. For both sites, connectivity to prefrontal, orbitofrontal and cingulate cortex correlated with OCD improvement. These results suggest that structural connections of focal stimulation sites to specific networks may lead to clinical benefit. Interestingly, the identified networks may differ not only by symptom but also based on the surgical target region.