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Tourette׳s disorder, also called Tourette syndrome (TS), is characterized by motor and vocal tics that can cause significant impairment in daily functioning. Tics are believed to be due to failed inhibition of both associative and motor cortico-striato-thalamo-cortical pathways. Comprehensive Behavioral Intervention for Tics (CBIT), which is an extension of Habit Reversal Therapy (HRT), teaches patients to become more aware of sensations that reliably precede tics (premonitory urges) and to initiate competing movements that inhibit the occurrence of tics. In this study, we used functional magnetic resonance imaging (fMRI) to investigate the neural changes associated with CBIT treatment in subjects with TS. Eight subjects with TS were matched with eight healthy controls in gender, education, age, and handedness. Subjects completed the Visuospatial Priming (VSP) task, a measure of response inhibition, during fMRI scanning before and after CBIT treatment (or waiting period for controls). For TS subjects, we found a significant decrease in striatal (putamen) activation from pre- to post-treatment. Change in VSP task-related activation from pre- to post-treatment in Brodmann׳s area 47 (the inferior frontal gyrus) was negatively correlated with changes in tic severity. CBIT may promote normalization of aberrant cortico-striato-thalamo-cortical associative and motor pathways in individuals with TS.

Tourette׳s disorder, also called Tourette syndrome (TS), is characterized by motor and vocal tics that can cause significant impairment in daily functioning. Traditionally, pharmacotherapy has been considered the first line of treatment for tic suppression. However, available medications often fail to bring about sustained remission, and many patients are reluctant to take medications because of possible unwanted side effects. Habit Reversal Therapy (HRT), a behavioral treatment, has become the nonpharmacological treatment of choice (Verdellen et al., 2011 and Steeves et al., 2012). In brief, the primary strategies of HRT consist of (a) awareness training (to help the patient detect tics as early as possible) and (b) competing response training (which encourages the patient to engage in a behavior that is physically incompatible with the tic, and thus prevents the tic from occurring). These strategies are often supplemented with (c) relaxation and (d) contingency management (e.g., a reward system to enhance treatment compliance). The efficacy of HRT has been evaluated in a number of smaller trials with promising results (e.g., Azrin and Peterson, 1990, Wilhelm et al., 2003 and Deckersbach et al., 2006). Recently, two large randomized multi-site trials funded by the National Institute of Mental Health (NIMH) investigated the efficacy of an expanded form of HRT, the Comprehensive Behavioral Intervention for Tics (CBIT). These two studies, one in children and the other one in adults, found that CBIT was associated with significantly greater reductions in tic severity and impairment relative to standardized psychoeducation plus supportive therapy (Piacentini et al., 2010 and Wilhelm et al., 2012). Treatment gains were well maintained at 6-month follow-up. The present study was a supplement to the study on adults with TS (Wilhelm et al., 2012). Specifically, we investigated the neural correlates of CBIT with functional magnetic resonance imaging (fMRI). Prior research indicates that tics are due to failed inhibition within cortico-striato-thalamo-cortical pathways (Mink, 2001). The basal ganglia, via thalamo-cortical projection neurons, facilitate the release of desired motor movements and the inhibition of unwanted motor movements. In TS, clusters of abnormally active striatal neurons within the basal ganglia lead to aberrant inhibition of neurons in the globus pallidus, pars interna (GPi; the major output of the basal ganglia). Increased inhibition of GPi neurons in turn disinhibits thalamo-cortical projection neurons, resulting in the release of unwanted motor patterns ( Mink, 2001). In addition, frontal regions appear to modulate aberrant cortico-striato-thalamo-cortical circuits in a top-down manner in the service of tic suppression (i.e., Casey et al., 1997, Bush et al., 1998, Peterson et al., 1998, Konishi et al., 1999, Rubia et al., 2001, Bunge et al., 2002, Fischer et al., 2003, Ridderinkhof et al., 2004, Serrien et al., 2005, Wright et al., 2005a and Wright et al., 2005b). The Visuospatial Priming (VSP) task has been repeatedly used to assess response inhibition (Swerdlow et al., 1996, Wright et al., 2005a and Wright et al., 2005b). Less inhibition and greater facilitation has been found in children and adults with TS, compared with healthy controls (Swerdlow et al., 1996). In addition, VSP performance is correlated with response to behavior therapy but not supportive psychotherapy for TS (Deckersbach et al., 2006). In the present study, participants with TS and healthy controls completed the VSP during fMRI scanning before and after CBIT treatment (or an equivalent waiting period for healthy controls) to investigate neural changes in the basal ganglia and frontal cortex associated with CBIT treatment

3. Results 3.1. Behavioral data The mixed model ANOVA analyzing reaction times revealed no main effect of group (TS vs. controls; F(1, 14)=0.86, p=0.37). There was a main effect of time (pre-CBIT and baseline for controls vs. post-CBIT and post-waiting period for controls). Both controls and TS subjects showed faster reaction times after compared with before CBIT and waiting period for controls, suggesting a practice effect (F(1, 14)=5.96, p=0.029; mean pre-CBIT RT=520.47 s, S.D.=19.95 s, mean post-CBIT RT=495.98 s, S.D.=20.88 s). There was also a main effect of prime (F(1, 14)=20.65, p<0.001). Pair-wise comparisons revealed that all participants had slower reaction times for negative prime trials compared with neutral trials and had faster reaction times on positive prime trials than neutral trials (mean RT for negative prime=531.24 s, S.D.=20.70 s, mean RT for positive prime=492.49 s, S.D.=20.80 s; mean RT for neutral=500.94 s, S.D.=18.83 s; Fig. 2). There were no significant interactions. Full-size image (45 K) Fig. 2. Visuospatial priming task performance before and after CBIT. TS patients and healthy controls (HC) did not differ on overall reaction times or percent accuracy, but both HC and TS subjects showed faster reaction times after CBIT compared to before CBIT (waiting period for HC), suggesting a practice effect (F(1, 14)=5.96, p=0.029). There was also a main effect of prime for reaction times (F(1, 14)=20.65, p<0.001) and percent accuracy (F(2, 28)=8.20, p=0.002). All participants had slower reaction times for negative prime trials compared to neutral trials and had faster reaction times on positive prime trials than neutral trials. Both TS subjects and healthy controls were also more accurate for the positive prime trials than the neutral trials, which were more accurate than the negative prime trials. Note. TS=Tourette׳s disorder; HC=healthy control; VSP=Visuospatial Priming task; neg=negative, neu=neutral, pos=positive. Figure options The mixed model ANOVA analyzing percent accuracy also revealed no main effect of group (TS vs. controls) (F(1, 14)=0.01, p=0.91). There was a main effect of prime; both TS subjects and healthy controls were more accurate for the positive prime trials than the neutral trials, which were more accurate than the negative prime trials (F(2, 28)= 8.20, p=0.002; mean accuracy for negative prime=91.84, S.D.=1.45, mean accuracy for positive prime=94.57, S.D.=0.95, mean accuracy for neutral trial=93.53, S.D.=1.16; Fig. 2). There were no significant interactions. 3.2. fMRI data 3.2.1. Group main effects For VSP task-related changes (VSP task vs. fixation), we did not find any significant between-group differences in our a priori regions of interest before or after CBIT/baseline for healthy controls. However, we found a significant interaction between group (TS vs. controls) and time (pre- vs. post-CBIT). As shown in Fig. 3, TS subjects showed a decrease in activation from pre- to post-CBIT and controls showed an increase in activation from pre- to post-waiting period in the putamen (MNI coordinates=−22, 0, 10, k=107, Z-score=3.67, p<0.001). For the TS subjects, this finding remained even after controlling for whether the TS subjects were taking medication or were medication-free (F(1, 13)=9.05, p=0.01). Full-size image (54 K) Fig. 3. Treatment associated putamen activation. For VSP task-related changes (VSP task vs. fixation), we found a significant interaction between group (TS vs. controls) and time (pre- vs. post-treatment) in the putamen (MNI coordinates=−22, 0, 10, k=107, Z-score=3.67, and p=0.016). Whereas TS subjects initially had greater putamen activation prior to treatment compared to controls, after treatment, TS subjects had less putamen activation than controls. Note. TS=Tourette׳s disorder; HC=healthy control; VSP=Visuospatial Priming task; MNI=Montreal Neurological Institute. Figure options There were no significant activations in a priori regions that exceeded AlphaSim correction for multiple comparisons specific to VSP negative priming or positive priming. 3.2.2. Neural correlates of treatment-related changes in tic severity and premonitory urges We also investigated correlations between the change in tic severity and premonitory urge levels (pre-CBIT minus post-CBIT YGTSS Total Tic and PUTS scores) and the change in VSP task-related activations from pre to post. We found a significant negative correlation between the change in YGTSS Total Tic scores and a region in BA 47 in the inferior frontal gyrus (MNI coordinates=56, 20, 0, k=35, Z-score=2.68, Pearson׳s r=−0.85, and p=0.007; Fig. 4). Changes in scores on the BDI, BAI, Sheehan Disability Scale, and ADHD Rating Scale from pre- to post-CBIT were not correlated with the change in putamen activation (all p values >0.16). However, the change in Y-BOCS scores was negatively correlated with the change in putamen activation, such that the greater the change in obsessive–compulsive symptoms, the less of a change in putamen activation from pre- to post-CBIT (Pearson׳s r=−0.81, and p=0.015). There were no significant correlations with changes in premonitory urge levels. Full-size image (21 K) Fig. 4. Treatment related change in tic severity in the inferior frontal gyrus. We found a significant negative correlation between the change in YGTSS Total Tic scores and a region in the inferior frontal gyrus (MNI coordinates=56, 20, 0, k=35, Z-score=2.68, Pearson׳s r=−0.85, and p=0.007). Note. IFG=inferior frontal gyrus; CBIT=Comprehensive Behavioral Intervention for Tics; YGTSS=Yale Global Tic Severity Scale; MNI=Montreal Neurological Institute. Figure options 3.2.3. Predictors of change in tic severity and premonitory urges We also conducted predictor analyses to see if initial YGTSS Total Tic scores and initial premonitory urge levels were significantly correlated with CBIT associated changes in VSP task-related activations (pre- minus post-CBIT) in our a priori regions of interest (BA 11, 44, 47, caudate, and putamen). Initial tic severity and premonitory urge levels were not significantly correlated with the change in VSP task-related activation in our a priori regions (all p values >0.62). Correlations between pre-treatment Y-BOCS, BDI, BAI, Sheehan Disability Scale, and ADHD Rating Scale scores and changes in activation in the putamen were nonsignificant (all p values >0.11). For a posteriori regions there was a significant positive correlation between initial tic severity and VSP task-related activation in the middle temporal gyrus (MNI coordinates=−62, −14, −8, k=722, Z-score=3.42, Pearson׳s r=0.94, and p=0.001) and a significant negative correlation between initial premonitory urge levels and VSP task-related activation in the superior temporal gyrus (MNI coordinates=50, 14, −16, k=601, Z-score=3.90, Pearson׳s r=−0.97, and p<0.001).