. This model
Environmental risk factors
Pathophysiology
Electrophysiology
Reduced short-interval cortical inhibition (SICI) in the primary motor cortex (M1) did not differ between children with and without TS, but correlated significantly with tic severity in the TS group, though not urge severity \citep{Batschelett_2023}.
Neuroimaging studies
Other
Data from brain imaging and transcriptomic research supports a hypothesis of disturbed iron metabolism in TS \citep{37292704}.
Libet's clock, Bereitschaftspotentials, and sense of volition \citep{37142497}.
Treatment
Psychological interventions
An intensive group format for delivering Exposure and Response Prevention (ERP) for TS was tested in a pilot study in 20 children, age 8-16, with encouraging results \citep{37210660}.
Pharmacological studies
"In this randomized clinical trial, ecopipam, a D1 receptor blocker, was more effective than a placebo in reducing tic severity in children and adolescents with Tourette syndrome. Ecopipam was well tolerated and did not cause weight gain or movement disorders." \citep{36628546a}.
Eagerly anticipated results of the CANNA-TICS study appeared in February, 2023 \citep{36878177}. "The authors performed a randomized, controlled trial of nabiximols in 97 adults with TS or chronic motor or verbal tic disorder. Befitting the study investigators' [a priori] view of the literature, people were randomized to drug or placebo in a 2:1 ratio. The primary, predefined efficacy endpoint was a tic reduction of at least 25% on the YGTSS total tic score after 13 weeks of treatment, a magnitude of change recognized as clinically meaningful improvement by an expert panel. The study did not show significant improvement by this measure. However, there were some indications of improvement, including a higher response rate (22% vs 9%) in the nabiximols group, a significantly greater reduction in self-reported tic severity on the Adult Tic Questionnaire, a numerically greater improvement of tics on a standardized video rating scale, and trends for improvement in quality of life and in impairment due to tics. There were no serious safety issues, with side effects of similar severity in 95% of those in the active drug group versus 79% of those in the placebo group (p=.03). Patients with ADHD or with worse general health were most likely to improve. Thirteen percent of patients at the site that enrolled over half the participants reported intentional or accidental unblinding on an end-of-study interview. Of course, other participants likely suspected their drug assignment; a forced-choice blindedness assessment is not reported. In sum, a reasonably large RCT showed hints of superiority for nabiximols over placebo, but the study did not meet the pre-specified treatment target." --quoted from \citep{Black_2023}. The authors are to be commended for timely publishing a technically negative study, but one with important clinical implications.
Fascinating initial results appeared in April from a Phase IIa study of isoallopregnanolone in 28 teens and adults with TS \citep{anonymous,america}. The mean reduction of YGTSS total tic score in the per-protocol drug group was 30%, vs. 13% in the placebo group. The active compound group similarly had greater improvement of tic-related impairment, quality of life and premonitory urges. Treatment was well tolerated. How this compound improves tics is not clear, since it interferes with the indirect GABA-enhancing effects of allopregnanolone, an endogenous neurosteroid that can improve anxiety or cause sedation. However, some rodent data is consistent with these results \citep{28611376}.
Either tiapride or topiramate appeared effective in a retrospective analysis of 126 children with TS \citep{36979193}
Small RCT shows significantly more improvement in tics with a THC + CBD combination than with placebo \citep{al2023}. The main side effects were cognitive / sedative in nature.
Neurosurgery
An open study of bilateral GPe DBS in 13 TS patients showed high responder rates and mean symptom improvements for tics, OCD, depression and anxiety at a mean of 5 years after implantation \citep{37294231}. Benefits of stimulation developed gradually from 10 days to 1 year after stimulation began. Stimulation tended to work better with the 2 dorsal contacts. Side effects were mild or transient.
Dual-site DBS for OCD and TS \citep{36863881}.
DBS evoked potentials for target optimization in OCD \citep{Waters_2023}.
Other treatments
A study of transcranial magnetic stimulation (TMS) applied to the left prefrontal cortex (BA 40) showed no evidence of benefit on tics \citep{Paulus_2023}.
Two randomized, controlled trials of median nerve stimulation (MNS) for treatment of tics appeared in 2023, further investigating the fascinating report by \citet{32502412}. The first was an in-laboratory crossover trial comparing repeated 1- or 5-minute sessions of 10 or 12 Hz stimulation in 32 people with a chronic tic disorder \citep{Iverson_2023}. Rhythmic MNS was given on one day for repeated stimulation-on and -off, 1- and 5-minute blocks, and arrhythmic MNS at the same mean frequency on another day. Either produced significant improvement in tics and premonitory urges, to a similar degree. Since only rhythmic stimulation increases contralateral sensorimotor cortex 12 Hz activity on EEG \citep{32502412} or MEG \citep{Houlgreave2022}, those effects must not be the mechanism of the clinical benefit.
The second MNS controlled trial was a parallel-group study of a wristwatch-style stimulation device \citep{37133932}. The active treatment used unilateral 10 Hz MNS at a current just above the threshold for activating movement of the thumb. A sham condition was MNS that began at the same current as the active treatment, but current was smoothly decreased by about half over the next minute. Both treatments were given for a total of 10 minutes (5 blocks of 2 min on, 1 min off) every morning for 4 weeks. Both treatments activated sensory nerve fibers, and participants were adequately blinded. A third, wait-list condition, was meant to measure the magnitude of the placebo response in the sham treatment group. During MNS, active MNS was superior to sham MNS and wait-list controls, and the latter two groups had approximately equal responses. Surprisingly, even though stimulation was only on for 10 minutes a day, clinical response "offline," i.e. YGTSS rated over the entire past week, was also clearly more effective with active MNS.
Tics, family and society