The present study identified a common pattern of gray matter brain tissue alteration in actually unmedicated adult patients with GTS and comorbid OCD and/or ADHD characterized by left inferior frontal gyrus decreases of GM volumes. There were no significant differences between healthy controls and GTS patients concerning a GM volume increase. Based on our results, we suggest that the left IFG may constitute a common underlying neurological correlate of GTS with comorbid OCD and/or ADHD. As can be seen in Figure 1, gray matter volume reductions of the left IFG in the whole group of GTS patients are predominantly observed in the subgroups of GTS patients with comorbid OCD. This possibly reflects the failure to control behavior and may be a key feature of persistent GTS and OCD in adults. The finding of left IFG decreases of GM volumes is in line with data from recent studies  including our own examining patients with GTS "only" and demonstrating volume reductions predominantly in different frontal areas . Thus, it is not surprisingly that in the present study volume reduction of the left IFG was pronounced in GTS patients with comorbid OCD/ADHD which suggests an additive effect. In particular, the left IFG has previously been associated as a key region for OCD . Together with the inferior parietal cortex it serves as a network responsible for the active inhibition of attentional processes. Additionally, this network has been associated with voluntary shifts of attention across sensory modalities . The precise location of this region is heterogeneous across studies, as it includes the most orbital part of the IFG and extends into the lateral orbitofrontal gyrus (sometimes used as synonyms). In OCD patients, functional alterations of this region have been observed, and a recent meta-analysis could associate these functional alterations to structural abnormalities . However, the neuronal mechanisms are still unknown, and even the direction of the functional-structural relationship is controversial. In the above mentioned meta-analysis  and in a study by van den Heuvel and colleagues , the lateral orbitofrontal cortex was found to be reduced in OCD patients compared to healthy controls, whereas a more recent meta-analysis, in which functional and structural findings were combined, showed greater gray matter density of the lateral orbitofrontal cortex in OCD . However, by using a different voxel-based meta-analytic method called signed differential mapping, Radua and Mataix-Cols  could not find any structural abnormalities of patients suffering from OCD in this area. They reported an association of gray matter volume increases in the basal ganglia with symptom severity in OCD.
But are there any functional changes of the left IFG in GTS? We are aware of only a single PET-study  reporting an abnormal positive coupling between the basal ganglia and the lateral orbitofrontal cortex. In fact, thirteen out of eighteen patients included in this study had comorbid OCD symptomatology suggesting that OCD pathology is a main factor of alterations in this frontal region. Our data corroborate the assumption that compensatory neuroplastic processes in terms of frontal cortex hypertrophy - that might help to compensate tics  as can be seen in GTS adolescents  - are absent or even reversed in adults with persistent tic disorders .
Our results of a comparison of the GTS subgroups with ADHD comorbidity to the GTS group without ADHD comorbidity (GTS and OCD) revealed a volume increase of the left amygdala which could also be observed in comparison to healthy controls. Structural alterations of the amygdala -gray matter volume increase in particular  - have been previously associated with compensatory mechanisms in GTS . The findings in pure ADHD adult groups have been equivocal so far . In children with GTS and comorbid ADHD symptomatology, a linkage between amygdalar volume reductions has been reported . It seems reasonable to assume that our finding of gray matter volume increase in the left amygdale reflects long-term structural mechanisms in order to compensate a delay in cortical maturation during childhood .
VBM analyses reflect a number of anatomical features, including gray matter alterations and shifts in gyral or sulcal anatomy. Therefore, it can be speculated that GM volume decreases observed in this study might be the consequence of malformated cortical development, such as abnormal neuronal migration. Future studies using different volumetric measurements such as an estimation of cortical thickness may further contribute to the underlying structural differences in GTS [19, 41].
Lack of findings in previously reported regions and limitations of the study
We failed to detect group differences in regions previously associated with GTS pathology including the basal ganglia [7–10] and the mesencephalon [13, 14]. These discrepancies may reflect sample characteristics (since we included only actually unmedicated adults GTS patients with comorbid OCD/ADHD) and different methodological approaches. For example, Ludolph  and Garraux  used predefined regions of interest and subsequently conducted small volume corrections. This analysis strategy assumes stationary smoothness, which may not even be appropriate for VBM . Additionally, it has been discussed that larger sample sizes (including up to 70-90 subjects) may be a prerequisite in order to detect volume differences of small subcortical structures . Thus, our failure to detect significant differences in these particular regions does not necessarily prove that these regions are indeed unaffected.
A limitation of the study was the small subgroup of only 4 patients with comorbid ADHD (without OCD). When excluding this subgroup from additional analyses, differences between GTS patients and controls even increase strengthening our assumption that GM volume reduction in the inferior frontal gyrus are mainly based on the presence of comorbid OCD. However, future structural studies including larger samples of patients with comorbid ADHD are needed to better clarify the impact of comorbid ADHD.
Although the group of patients and the control group were not comparable in regard to IQ, we do not think that group differences can be explained by these small IQ differences, since - to the best of our knowledge - there are no VBM studies available reporting morphological alterations on the basis of small group differences in intelligence. Our results are in line with recent findings in children demonstrating that IQ scores in patients with GTS "plus" (with comorbidities) are slightly reduced compared to healthy .
Although all patients included in this study were unmedicated for at least 6 months prior to MRI imaging, some patients were medicated with typical or atypical antipsychotics before. In patients with Tourette syndrome, it has been demonstrated that neuroleptic medication increases both caudate and globus pallidus volumes . Because in patients with schizophrenia it has been demonstrated that medication effects are reversible [45, 46], we speculate that in the present study possible influences of antipsychotic medication on brain volumes can be excluded. However, to the best of our knowledge, in patients with GTS no longitudinal studies are available investigating neuroleptic-induced volume changes after withdrawal from medication.
Gray matter volume correlations with clinical scores
We found several significant correlations between GM volumes and different clinical scores. Tic severity (RVTRS) correlated negatively with GM volumes of both the left insula and the right premotor cortex. Although, video-based tic ratings represent only a short period of time, they are regarded as the most objective tic measurement. Since in adult patients, spontaneous tic fluctuations are less marked compared to children, it can be speculated that the RVTRS indeed represents tic severity in an individual patient.
This result is in line with recent morphological  and functional [48, 49] findings in GTS patients emphasizing an involvement of the insula in tic generation. Furthermore, in people with persistent and routine habits an involvement of this brain area has been found supporting the hypothesis of an insula-striatal neural interplay during the preference of default behavior . The premotor cortex has also been described before as a brain region that is involved in GTS pathology demonstrating abnormal metabolic networks . Additionally, it was recently suggested that cortical thinning in premotor areas is correlated with more complex tics in GTS adults .
In line with findings of a recent study in patients with "pure" OCD , we found a negative correlation between the severity of OCD (Y-BOCS) and the left postcentral gyrus. In "pure" OCD an involvement of different brain areas including both the (orbito-) frontal cortex and the anterior cingulate cortex, as well as subcortical structures such as the thalamus and caudate nucleus has been suggested [53, 54]. However, there is evidence that in different symptom dimensions of OCD different brain networks might be involved . For example, functionally decreased activity in the left postcentral gyrus has been found in patients with obsessions/checking rituals but not in those with cleanliness/washing rituals . It is well known that in patients with GTS plus OCD a different OCD symptom subtype occurs compared to patients with "pure" (tic-free) OCD: While obsessions/checking rituals are relatively common in GTS patients, aggressive repetitive thoughts, contamination worries and washing behaviours are rare . Thus, our finding of a negative correlation between OCD severity and GM volume of the left postcentral gyrus further supports an involvement of this brain area in the pathology of OCD in GTS patients. In addition, it can be speculated that comparable brain areas are involved in those patients with the OCD subtype obsessions/checking rituals and GTS patients with comorbid OCD suggesting a common underlying pathophysiology.
In contrast, we found a positive correlation between the severity of ADHD (assessed by the symptom checklist, CAARS, and WURS-K) and bilateral GM volumes in the putamen. This finding is in line with results obtained from recent MRI studies in children with "pure" ADHD consistently demonstrating an involvement of the putamen [57, 58] with unilateral or bilateral GM volume reduction in this brain area. Structural studies involving adults with ADHD are limited and resulted in contradictory data (for an overview see ). It can be speculated that differences regarding GM volume sizes in children with ADHD compared to adults with ADHD are related to developmental neuroplastic processes. Comparable findings with opposite volume changes in children and adults have been demonstrated in patients with GTS [24, 29]. Our results further support the hypothesis that the basal ganglia, and in particular the putamen, are involved in the pathophysiology of ADHD, since this region has been associated with diverse cognitive functions (e.g., language, learning and memory, attention and control of behavioural responses) . In addition, our finding of a correlation between ADHD severity and GM volume of the putamen in patients suffering from GTS is in line with the assumption that the coexistence of ADHD and GTS represents an additive rather than an interactive or phenotype model .