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## Treatment
In addition to the more focused reports below, a review \citet{Jankovic_2015} provided an overview of
treatments for tics appeared recently \citep{Jankovic_2015}. tic treatments.
### Psychotherapy
2015 saw several practical advances in psychotherapeutic treatment for tics. [TicHelper.com](http://www.tichelper.com/) is a commercial adaptation of Comprehensive Behavioral Intervention for Tics (CBIT) to the Internet, discussed at the [London congress in 2015](http://www.webcitation.org/6gWlBTYcC) \citep{Himle:TicHelper:London}. It is potentially an important treatment option, especially for the many TS patients who do not live near a behavior therapist. Efficacy testing is ongoing (see
[ClinicalTrials.gov](https://www.clinicaltrials.gov/ct2/show/NCT02413216)). [the trial summary at ClinicalTrials.gov](https://www.clinicaltrials.gov/ct2/show/NCT02413216)).
Additional information on CBIT effectiveness was recently provided. \citet{25988365} dug into the data from 2 previously reported, pivotal, randomized controlled CBIT studies that together enrolled over 200 children and adults to address the question of which types of tics responded best to CBIT treatment. Looking at specific tics across all subjects, the superior treatment benefit from CBIT compared to a control therapy could be attributed to differential improvement in only a few types of tics, including throat clearing and complex tics. However, tics that actually bothered people, most of which involved a premonitory urge, were more likely to respond preferentially to CBIT than to the control therapy. This result is not unexpected, since CBIT focuses first on bothersome tics, and preferably those preceded by a premonitory urge. This report also extends previous information about premonitory phenomena; about 40-60% of patients with any specific tic reported a premonitory urge for that tic.
...
A small, uncontrolled open trial of mindfulness-based stress reduction was provided to 18 individuals who were at least 16 years old \citep{25149879}. Treatment consisted of 8 weekly 2-hour group classes and one four hour retreat. Participants were taught a tic-specific meditation exercise that involved noticing any urges to tic while maintaining a focus on one's breathing rather than trying to change or eliminate the urge to tic. Only one subject dropped out and overall tic severity was decreased by 20% for the participants who completed the program. Ten subjects were rated as "much improved" or "very much improved" and thus considered treatment responders. The gains for the treatment responders were maintained at a one month follow-up visit suggesting that improvements reflected more than just the waxing and waning pattern commonly associated with tic severity.
An open-label trial of
psychotherapy, psychotherapy using a cognitive psychophysiological model of tic behavior, was conducted with 102 adults who had TS or chronic tic disorder \citep{26250742}. Ten weeks of individual psychotherapy involved a variety of components including increasing awareness of tics, muscle discrimination, decreasing muscle tension and an overactive style of action, identifying low and high risk activities in terms of tic probability, highlighting the differences in behaviors, thoughts and
feelings; feelings, and decreasing perfectionistic beliefs linked to tension and relapse prevention. These psychotherapy components were chosen because of
that group's prior research suggesting that some TS subjects have perfectionist beliefs when they plan actions and this leads to an impulsive overactive style resulting in frustration, tension and tics. Large effect sizes were seen for both treatment groups (TS, CTD) compared to the waiting list controls. 65% of the chronic tic disorder group and 74% of the TS group had reductions of more than 35% on the Tourette Syndrome Global Scale. At the end of treatment 78 of 85 completers were rated as having no more than mild symptoms, regardless of the starting severity, while the other 7 were considered to have moderate symptoms. Large effect sizes were seen whether tics were simple or complex, and similar results were seen for various tic locations
(i.e., eyes, (eyes, face, head, neck and shoulder, trunk and
abdomen; abdomen, or phonic). \citet{26022060} examined the effects of this psychotherapy approach on event-related potentials and lateralized readiness potentials (LRPs). EEGs were recorded for 20 TS subjects and 20 control subjects matched for age, sex and intelligence, while performing a stimulus-response compatibility inhibition task. During the
NoGo No-Go condition, the TS group exhibited a delayed and overactivated frontal late positive component. The authors interpreted this result as evidence that this frontal activation may be an adaptive mechanism that allows patients to perform similarly to the control subjects in terms of their behavioral performances. TS subjects exhibited delayed stimulus-locked LRP (sLRP) onset. TS subjects also displayed larger response-locked LRP (rLRP) peak amplitudes, which are associated with the execution of the motor program for the correct response. The authors suggest that the larger amplitudes may reflect overactivation of the premotor and motor cortex in TS patients. Although sLRP onset and rLRP peak normalized after psychotherapy, the larger sLRP amplitude
was did not.
Given the high rate of OCD comorbidity among TS patients, it is encouraging that more research is examining similarities and differences between OCD patients with and without tics. Tic status was evaluated using the YGTSS in a psychotherapeutic study of 124 children and adolescents with OCD who had shown a partial response to a serotonin reuptake inhibitor \citep{26126872}.
Although tics Tics were identified in 53% of the study participants,
but these subjects did not differ significantly from
non-tic tic-free participants in terms of age,
six, sex, family history, or OCD impairment or severity.
Cognitive-behavioral therapy resulted in similar OCD symptom improvement in both groups. The high rate of tics in this sample is partially explained by the inclusion of subjects with tics for less than one year.
Cognitive-behavioral therapy resulted in similar OCD symptom improvement in both groups. In another
study \citep{26091197}, study, 12 children and adolescents with tics whose OCD symptoms had not improved after 14 weeks of cognitive-behavioral therapy received either 16 weeks of sertraline treatment or 10 additional sessions of
CBT. Internalizing CBT \citep{26091197}. Externalizing disorders were more common in the
tic patients (50%) than in the non-tic
patients, patients (5.3%), while
externalizing internalizing disorders were more common in the
tic patients (50%) than in the non-tic
patients (5.3%). patients. The tic patients showed more improvement when switched to sertraline rather than additional CBT, while the non-tic patients showed similar improvement with either treatment. The authors suggested that the dopaminergic action of sertraline might have helped the OCD patients with tics; alternatively one might conclude simply that pediatric OCD patients with tics respond differently to treatment than do those
without. without tics.
### Medication
Efforts to maximize the value of pharmacological treatment continues. One of our colleagues highly recommended the following review of current medication treatment practice in Germany: \citep{24888751}. These researchers examined psychotropic prescriptions issued in Germany between 2006-2011 for children and adolescents who had been diagnosed with a tic disorder. There was only a slight increase in the number of prescriptions overall issued in 2011 compared to 2006. The mostly frequently prescribed medications were ADHD medications. Antipsychotics were the next most frequently
prescribed, with second generation prescribed; second-generation antipsychotics
being were more frequently prescribed over this time
period along period, with a relative increase in risperidone prescriptions
over the same period of time. Tic disorder patients specifically. Patients with a TS diagnosis were
the group most more likely to receive psychotropic
medication. medication than were children with other tic diagnoses.
A meta-analysis of 22 studies involving 2,385 children found no causal relationship between stimulants and tic onset although tics were associated with ADHD itself (5.7% in the psychostimulant groups and 6.5% in the placebo groups) \cite{26299294}. This summary of previous evidence hopefully can further reassure patients and prescribers that methylphenidate products do not cause
tics. tics (the evidence is less clear for amphetamine products).
Four patients with treatment-refractory TS were studied in [this early
report](http://ir.catalystpharma.com/releasedetail.cfm?ReleaseID=919254) report](http://www.webcitation.org/query?url=http%3A%2F%2Fir.catalystpharma.com%2Freleasedetail.cfm%3FReleaseID%3D919254&date=2016-05-09) of results using medication from the GABA-aminotransferase inhibitor class. One patient had a clinically significant reduction in tics while two others had tic reduction of approximately 25% but did not report subjective clinical improvement.
### Neurosurgery
Now that deep brain stimulation (DBS) is being used more frequently there have been efforts to standardize clinical treatment protocols in terms of patient selection and to standardize studies on effectiveness and efficacy. A revised consensus statement on DBS in TS appeared recently \citep{25476818}. It provides an important update to the 2006 recommendations \citep{16991144}, guided by almost a decade of generally positive results from an increasingly varied set of patients, though with limited evidence from randomized allocation treatment studies. Several major changes were made in the recommendations. First, the recommendation that DBS patients be 25 years or older has been replaced by a focus on clinical symptoms and severity. However, at a minimum, local ethics committee involvement was recommended for patients under 18 years of age. The second major modification in the guidelines was that a patient have a caregiver who would be available to accompany the patient to frequent follow-up appointments. In addition, the group recommended absence of active suicidal or homicidal ideation for 6 months prior to surgery. The final change in the guidelines
was the importance of recommended identifying and addressing personality disorders, malingering, factitious symptoms, embellishment, and other factors that can substantially complicate assessment or treatment.
Fourteen patients were randomly allocated to DBS on-stimulation or off-stimulation conditions for the first 3 months after
GPi DBS
surgery, leads were placed in the GPi (globus pallidus, pars interna), followed by a switch to the other condition for another 3 months \citep{25882029}. Ratings were collected blind to stimulation status.
A total of 13 Thirteen patients completed assessments in both blinded periods. This was followed by open-label stimulation adjustments for both groups. Total YGTSS scores were 15% lower at the end of the on-stimulation period compared with the off-stimulation period (p=0.048). Three serious adverse events occurred (two infections
in with the DBS hardware and one episode of hypomania during the blinded
on-stimulation stimulation on condition). This study is
praiseworthy because important as it provides evidence of
the efficacy in an on *vs* off stimulation, randomized, controlled design.
A case study raised the issue of temporary DBS treatment \citep{26290773}. The patient started having simple motor tics at the age of 7 followed by vocal and complex motor tics two years later. The patient also had ADHD and learning difficulties. Thalamic DBS surgery was provided when he developed continuous motor and vocal tics that resulted in his leaving school at the age of 17. A year after surgery his YGTSS score had decreased by 58%. Three years after the surgery the tic severity increased and the IPG was replaced, again followed by improved tic severity. When the patient was 23 it was noticed that the IPG was not operational, yet there had not been any increase in the patient's symptoms. After the device was left off for 2 years and the patient remained stable clinically, the decision was made to remove the device and the patient was still stable 8 months later. This case raises important questions discussed in the consensus statement \citep{25476818}, but without adequate controls, it is impossible to know whether DBS was the cause of tic improvement.
\citet{26180116} reviewed electrophysiological data obtained in nonhuman primate models of TS and in Parkinson disease, with the hope of identifying possible mechanisms to account for the efficacy of high-frequency
GPi-DBS GPi DBS in both a hyper- and a hypokinetic movement disorder. This article focuses on the possibility that excessive synchrony and pathological low-frequency oscillations (LFO) impair activation in the motor regions that receive input from the basal ganglia. There is also some evidence that synchronous oscillatory activity and excess LFO contribute to TS. DBS effectiveness is considered to occur because population-scale firing rates are maintained allowing proper encoding of desired movement. When used with Parkinson patients, DBS suppresses excess LFO in the GPE in addition to the GPI. GPI-DBS is theorized to suppress the phasic activations in the GPe and phasic inhibitions in the GPi for TS patients. It is hypothesized that in both medical conditions aberrant output is minimized while the population-averaged firing rate is maintained.
\citet*{26110808}
have provided a general review of reviewed DBS for movement disorders
generally and
also describe some
of the recent technological advances (i.e., electrode design; rechargable implantable pulse generators;
closed-loop,adaptive,stimulation). closed-loop, adaptive stimulation). \citet{25882028} discuss various obstacles to carrying out randomized, blinded studies of DBS with appropriate controls. \citet{25925326} summarize research describing
the effects of DBS on neural abnormalities associated with
TS TS, and
the effects of DBS. They also discuss how the findings relate to models of cortico-basal ganglia function.
### Other treatment
Lisanby and colleagues reported a careful, randomized controlled trial of repetitive transcranial magnetic stimulation (rTMS) aimed at supplementary motor area (SMA) in 20 adults with TS \citep{25912296}. There were suggestions of improvement, but on average, patients in the sham treatment group improved almost as much as those in the active treatment group. However, rTMS most effectively stimulates superficial regions of cortex, and an Israeli group employed this coil in an open-label study of 12 patients with treatment-refractory TS \citep{25342253}. The patients as a whole did not improve significantly, but a _post hoc_ analysis showed benefit in the 6 patients who also had OCD, and the treatment was well tolerated. A double blind, sham-controlled study in TS patients with OCD will be needed to confirm efficacy.
An open label trial of cranial electrical stimulation (CES) treatment was provided to 42 children with TS who were less than 12 years old \citep{25546850}. The patients applied electrodes to their earlobes when they went to bed so that they could receive the treatment on a daily basis for 24 weeks. Treatment was provided for 60 minutes and they could go to sleep if they wanted. Only one child dropped out before the completion of A review discusses the
study. The mean YGTSS score significantly decreased from 26.3 when they were initially seen to 11.4 after 24 weeks possible relevance of
treatment. fMRI scanning was optional and only 8 subjects completed the scans before and after treatment. Independent component analysis with hierarchical partner matching was used to examine functional connectivity among regions within the cortico-striato-thalamo-cortical circuit followed by Granger causality to examine effective connectivity. After neurofeedback for the
CES treatment
this subsample had stronger functional activity and connectivity in the anterior cingulate cortex, caudate and posterior cingulate cortex of Tourette syndrome and
weker activity in the supplementary motor area. These results must suggests that it may be
viewed as preliminary, since an RCT is required most useful to
rule out spontaneous improvement. treat TS children and adults who also have ADHD \citep{25616186}. \citet{26074752} summarize evidence suggesting that autonomic dysfunction may have a role in both epilepsy and Tourette Syndrome. This
articles article also summarizes attempts to use electrodermal activity (EDA) biofeedback to treat both conditions and describes the challenges that are presented by TS in using this type of intervention. EDA biofeedback, which consisted of 12 sessions over 4 weeks, produced at least a 50% reduction in seizures in more than half of the epileptic subjects and also produced changes in Contingent Negative Variation, which is modulated by changes in peripheral autonomic activity. Based on seizure diaries that were kept by a subset of the patients, these improvements were maintained over a period of years. These results were replicated in a 2014 study by another research group. In contrast, when a similar EDA biofeedback protocol was used with TS subjects \cite{24674962}, TS patients in the active and sham biofeedback groups were not able to reduce their sympathetic activity. Despite this, both the active-biofeedback and sham-control groups had significant decreases in tic frequency and obsessive-compulsive disorder symptoms, plus improvements in quality of life related to OCD symptoms.
A review discusses the possible relevance of neurofeedback for the treatment of Tourette syndrome and suggests that it may be most useful to treat TS children and adults who also have ADHD \citep{25616186}.
Researchers have also studied complementary and alternative (CAM) treatments. An open label trial of cranial electrical stimulation (CES) treatment was provided to 42 children with TS who were less than 12 years old \citep{25546850}. The patients applied electrodes to their earlobes when they went to bed so that they could receive the treatment on a daily basis for 24 weeks. Treatment was provided for 60 minutes and they could go to sleep if they wanted. Only one child dropped out before the completion of the study. The mean YGTSS score significantly decreased from 26.3 when they were initially seen to 11.4 after 24 weeks of treatment. Functional MRI scanning was optional and only 8 subjects completed the scans before and after treatment. Independent component analysis with hierarchical partner matching was used to examine functional connectivity among regions within the cortico-striato-thalamo-cortical circuit followed by Granger causality to examine effective connectivity. After the CES treatment this subsample had stronger functional activity and connectivity in the anterior cingulate cortex, caudate and posterior cingulate cortex and weaker activity in the supplementary motor area. These results must be viewed as preliminary, since an RCT is required to rule out spontaneous improvement.
Another CAM treatment undergoing initial efficacy testing is an oral orthotic device with which some patients have reported success. The rationale and design of the study, and initial safety results, were [reported at the London meeting](http://www.webcitation.org/6hNT4PRxf), and efficacy testing continues (see [the trial summary at ClinicalTrials.gov](https://clinicaltrials.gov/ct2/show/NCT02067819)).
