Cognitive function and decision-making in Tourette syndrome
\citet{28820427a} provide an updated and exhaustive review of neuropsychological aspects of TS (compare \citep{19913655}). The review highlighted the slight alteration of social cognition as well as more frequent learning difficulties and disabilities in children with TS. Recent data seem also confirm the deficit in executive function in TS as indexed by poor performance in continuous performance test and Stroop tests. Interestingly, using longitudinal evaluation of executive function in children with TS, \citet{28965812} showed that tic reduction was related to the development of the executive functions components associated with response inhibition, and that patients with remitted TS performed at normal or even higher levels. In contrast, the attentional and memory capacity seems to be impacted by comorbid symptoms more than TS per se. Sample size (n=122) or the healthy control group may explain different results obtained by \citet{Abramovitch2017}, who studied treatment response in TS. They concluded that "the finding that significant change in symptom severity of TS/CTD patients is not associated with impairment or change in inhibitory control regardless of treatment type suggests that inhibitory control [as measured by the tests selected] may not be a clinically relevant facet of these disorders in adults." Given these contradictory results, Morand-Beaulieu et al. review the puzzling question of inhibitory control in TS in a recent meta-analysis, and find larger inhibitory deficits in TS + ADHD patients, but this deficit was also present in "pure" TS \citep{Morand-Beaulieu2017}. This deficit in TS was most prominent in verbal responses, was associated with tics severity as assessed with YGTSS total tics score and was larger in studies that included medicated TS patients.
\citet{28740149b} study decisional capacities in TS and specifically the ability to learn from the outcomes of alternative courses of action (known as counterfactual learning). Unmedicated patients with TS showed normal performance on this task, whereas alteration was found in TS patients treated with the dopamine D2-like receptor (D2R) partial agonist aripiprazole, suggesting that modulating D2Rs may impair certain aspects of human reinforcement learning.
The Committee on Research of the American Neuropsychiatric Association published a systematic review on the neurobiology of the premonitory urge in TS \citep{28121259}. Conceição and colleagues proposed a computational model that attempts to link urge and tic phenomenology with functional anatomical evidence implicating somatosensory cortex and insula \citep{29017141}.
Electrophysiology
\citet{28798371} reported on enhanced multi-component behaviour in TS, which was also reflected in a smaller P3 event-related potential measured by EEG and potentially related to chronic tic control in these patients. An EEG study during simulated driving found that "mind wandering" may be quantifiable using EEG measures of alpha power and the P3a component of an auditory event-related potential (ERP) \citep{Baldwin_2017}. Since mind wandering is a defining feature of ADD, in addition to being ubiquitous during repetitive tasks, these measures may prove useful in studying ADHD phenomenology in tic disorders.
Neuroimaging studies
Polyanska and colleagues provide a meta-analysis of task-based neuroimaging reports in TS \citep{28831377}. Adults with TS show some impairment in lateralized sequential finger tapping movements, and this impairment was compared to fractional anisotropy of white matter tracts connecting primary motor cortex (M1) to M1 and supplementary motor area (SMA) to SMA \citep{28708864}.
Previous in vivo MRI studies of basal ganglia volume and shape in TS have produced differing results (reviewed in \citealp{27777415a}). A study of 47 children age 8-12 with TS, and controls with or without ADHD, found no significant group differences \citep{27862303}.
A PET study of the microglial activating marker TSPO in OCD found elevated TSPO concentrations in dorsal caudate, orbitofrontal cortex, thalamus, ventral striatum, dorsal putamen, and anterior cingulate cortex \citep{28636705}. Concentrations in patients were about 1/3 higher than in controls. This report implicates low-level brain inflammation in the pathophysiology of OCD.
Pharmacological studies
A study in unmedicated TS patients versus those taking the dopamine D2-like partial agonist aripiprazole show that this medication may impair learning from outcomes not chosen \citep{28740149}.
Clinical and neuropsychological studies
The Montréal group published a review of neuropsychological studies of TS \citep{28820427}. A study using the alternating serial reaction time task found no impairment of procedural learning in TS or ADHD \citep{28710940}. This result is surprising, given that habit learning on a "weather prediction" task is slower in TS \citep{11931939,15583117}, but may indicate that the two tasks engage different learning systems, a conclusion supported by the generally normal cognitive function in TS.
Münchau and colleagues extended their previous work on echopraxia (imitation) to children with TS \citep{28801946}. Participants were asked to lift either their index or pinky finger when prompted by an auditory tone; simultaneously they were shown a compatible or incompatible visual stimulus. Children with TS were slower overall but thereby gained less interference from the incompatible stimulus. The authors conclude that these results suggest that children with TS may employ "different or additional inhibition strategies" than children without tics. Again, on this task children with TS show superior, not deficient, action inhibition.
Treatment
\citet{28451624} review treatments for tic disorders.
Psychological interventions
\citet{Houghton2017} analyzed their existing data to understand whether premonitory urges decreased in youth (N = 126) and adults (N = 122) with persistent tic disorders who had participated in parallel randomized clinical trials comparing behavior therapy to psychoeducation and supportive therapy. The prediction was that urge severity would decrease in those who responded to behavior therapy. Surprisingly, reductions in premonitory urge severity did not mediate the relationship between treatment and outcome in either adults or children, regardless of treatment modality. The authors conclude that habituation is not the therapeutic process underlying the effectiveness of behavior therapy. This important result warrants further study.
Another report from the same data set examined what clinical features at baseline predicted improvement in tics during treatment CBIT \citep{28202705}. Importantly, those treated with CBIT improved regardless of medication status, while in the control (supportive therapy) group, tics improved only in those taking medication for tics. Also importantly for the understanding of behavior therapy in TS and patient selection, other psychiatric symptoms, age, sex, family functioning, and expectation of improvement had no significant effects on benefit from therapy. And contrary to some opinions, patients with worse tic severity had significantly better improvement in tics with CBIT. Anxiety disorders and, surprisingly, more severe premonitory urges predicted less improvement.
O'Connor and colleagues published a book describing their combined psychotherapeutic approach to tics \citep{OConnor2017book}.
Several groups reported efforts to increase dissemination and use of behavior therapy for tics. An internet-based, therapist-guided behavior therapy for tics is being studied in the
BiP-TIC project, discussed
here. The TicHelper.com internet-based CBIT program went live in late 2017 and received a positive review
\citep*{28966546}.
Medication
A group of international experts provided a status report and recommendations for using brain imaging for the rational development of novel psychopharmacological interventions \citep{28031269}. As an example, a fascinating study in pediatric ADHD showed that fMRI response to a cognitive task (Go/No-Go) strongly predicted better clinical response to methylphenidate than to atomoxetine \citep{28647012}. As the authors conclude, "These data do not yet translate directly to the clinical setting, but the approach is potentially important for informing future research and illustrates that it may be possible to predict differential treatment response using a biomarker-driven approach."
Initial results from the first randomized, controlled trial (RCT) with a dopamine D1 receptor antagonist in pediatric TS were released by the sponsor in January, 2017 \citep{chipkin:2017}. These new results supported the positive results from a pilot study in adults with TS \citep{24434529}, and suggest a novel treatment mechanism for tics.
In April, the US FDA approved the presynaptic dopamine depleting agent valbenazine (Ingrezza®) for treatment of tardive dyskinesia
\citep{NBI:pressrelease}. Tourette syndrome is a likely off-label use for the drug, as the company has been conducting studies in children and adults with TS (
ClinicalTrials.gov). The FDA designated valbenazine an orphan drug for pediatric patients with TS
\citep{syndrome}. Another VMAT–2 inhibitor, tetrabenazine, has been used for some time in the treatment of TS
\citep{4281483,4613321,27819145}, and a related compound, deutetrabenazine
\citep{28387387}, showed initial positive results in TS
\citep{27917309}; the FDA approved it for treatment of tardive dyskinesia in August
\citep{Austedo:approval}.
Aripiprazole has become a drug of choice in treating tics and comorbidities in TS over the past decade. However, large scale trials have been missing. Moreover, aripiprazole is not marketed for children and adolescents in many countries, regardless of the indication. \citet{Sallee2017} report on a phase 3, randomized, double-blind, placebo-controlled trial in 133 pediatric patients randomized in a 1:1:1 ratio to low-dose aripiprazole (5 mg/day if <50 kg; 10 mg/day if ≥50 kg), high-dose aripiprazole (10 mg/day if <50 kg; 20 mg/day if ≥50 kg), or placebo for 8 weeks. The primary efficacy endpoint was mean change from baseline to week 8 in the Yale Global Tic Severity Scale Total Tic Score (YGTSS-TTS). The Clinical Global Impression-Tourette's Syndrome improvement score was also evaluated. High-dose aripiprazole was more efficient than low-dose aripiprazole, and both were superior to placebo. Importantly, tolerance was overall good and no serious AEs or deaths occurred, indicating that oral aripiprazole is a safe and effective treatment for tics in children and adolescents. These results provide important reassurance to clinicians who have been using aripiprazole for TS for years now. The placebo response rate (for the Clinical Global Impression scale), though half the response rate in the active treatment groups, was nevertheless surprisingly high (38%).
A small (
N=34) RCT of guanfacine showed no meaningful difference in effects on tic ratings or clinical impressions of improvement between the drug and placebo groups
\citep{28723227a}. This result is important and surprising, given that adrenergic α2 agonists have been seen as first-line treatment for TS, especially in TS patients with ADHD
\citep{26786936}. Both these studies show how important RCTs are to clinical care in TS. Speaking of RCTs and guanfacine, a
press release reported that extended-release guanfacine showed superiority to placebo in adults with ADHD (discussed
here). The importance of this report comes primarily from the scarcer data on ADHD treatments in adults
vs. children.
Neurosurgery
A fascinating study demonstrated in mice that interfering electrical "beats" (such as the beats one hears when tuning one instrument to another) can be used to steer neuron activation to focal sites in the brain without surgical electrode implantation \citep{28575667a}. Much work remains to be done to demonstrate feasibility, safety and efficacy in humans, but this potentially could lead to noninvasive, focal brain stimulation.
\citet{Welter2017} performed a randomised, double-blind, controlled trial on DBS of the posterior and anterior internal globus pallidus for severe TS. The design was very similar to that reported in 2015 by \citet{25882029}, and so were the results. The primary endpoint was the difference in Yale Global Tic Severity Scale (YGTSS) score between the beginning and end of the 3 month double-blind period. No significant differences between groups were noted in YGTSS score change between the beginning and the end of the 3 month double-blind period, despite a slight improvement in the stimulated condition. However, after the end of the open stimulation period and further parameter adjustment, results become significant compared to baseline. Also, when turning the stimulators off in a blinded fashion, YGTSS scores increased again to reach near baseline levels. Overall, this study is most important in terms of optimal study design. The stimulator programming period preceding the blinded phases was likely too short and the parameters suboptimal (a choice intended to reduce unblinding). Future studies will need to consider these results carefully.
A London center reported an analysis of GPi DBS data, looking for the "sweet spot" for DBS for tic improvement \citep{28787721}. They report that "a region within the ventral limbic GPi, specifically on the medial medullary lamina in the pallidum at the level of the AC-PC, was significantly associated with improved tics but not mood or OCB outcome." Two patients with DBS to the fields of Forel experienced a good outcome \citep{28659777}.
TS patients undergoing deep brain stimulation, independent of the surgical target, usually require high stimulation parameters, leading to short (2-3 years) battery life, meaning frequent and costly battery replacements. Michael Okun and colleagues showed proof of the principle that triggered rather than continuous DBS may be helpful \citep{28960154}. In a single patient with medically refractory TS, a spectral feature in the 5- to 15-Hz band was used as the control signal from bilateral leads in the centromedian-parafascicular (Cm-Pf) region of the thalamus. Significant tic improvement compared to baseline was observed 12 months after the procedure, similar to that obtained with continuous DBS, and resulted in a 63% improvement in the neurostimulator's projected mean battery life. These so called closed-loop systems are gaining traction in various CNS diseases where DBS is applied, and this case reports paves the way in TS.
A report from the deep brain stimulation (DBS) group in the Netherlands called attention to side effects over the course of treatment in TS patients with thalamic DBS \citep{28102636}. A subthalamic nucleus (STN) DBS study in OCD reminds us that DBS can cause side effects; STN stimulation at higher voltages caused chorea-ballismus \citep{28532905}.