- Research article
- Open Access
Lateral frontal cortex volume reduction in Tourette syndrome revealed by VBM
© Wittfoth et al; licensee BioMed Central Ltd. 2012
- Received: 20 September 2011
- Accepted: 14 February 2012
- Published: 14 February 2012
Structural changes have been found predominantly in the frontal cortex and in the striatum in children and adolescents with Gilles de la Tourette syndrome (GTS). The influence of comorbid symptomatology is unclear. Here we sought to address the question of gray matter abnormalities in GTS patients with co-morbid obsessive-compulsive disorder (OCD) and/or attention deficit hyperactivity disorder (ADHD) using voxel-based morphometry (VBM) in twenty-nine adult actually unmedicated GTS patients and twenty-five healthy control subjects.
In GTS we detected a cluster of decreased gray matter volume in the left inferior frontal gyrus (IFG), but no regions demonstrating volume increases. By comparing subgroups of GTS with comorbid ADHD to the subgroup with comorbid OCD, we found a left-sided amygdalar volume increase.
From our results it is suggested that the left IFG may constitute a common underlying structural correlate of GTS with co-morbid OCD/ADHD. A volume reduction in this brain region that has been previously identified as a key region in OCD and was associated with the active inhibition of attentional processes may reflect the failure to control behavior. Amygdala volume increase is discussed on the background of a linkage of this structure with ADHD symptomatology. Correlations with clinical data revealed gray matter volume changes in specific brain areas that have been described in these conditions each.
- Gilles de la Tourette syndrome
- Voxel-based morphometry
- Inferior frontal gyrus
- Obsessive-compulsive disorder
- Attention deficit hyperactivity disorder
Gilles de la Tourette syndrome (GTS) is a complex chronic motor and vocal tic disorder with childhood onset. However, the majority of patients, in addition, suffer from different comorbid disorders, most often obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) [1, 2]. On average, 20-60% of all GTS patients have comorbid OCD, while about 50% suffer from ADHD . In contrast, GTS "only" - without any comorbidity - occurs in only 10 to 15% [4, 5]. Previous structural imaging studies investigating gray and white matter abnormalities in GTS revealed conflicting results. It has been suggested that these inconsistent data are mainly related to differences in patients' age, gender, handedness, medication status, comorbidities, imaging techniques, and analysis strategy. Despite these discrepancies, there is substantial evidence that structural alterations in several brain regions are indeed related to the pathology of GTS (for an overview, see also ). Most of these changes corroborate the hypothesis of alterations in cortico-striato-thalamo-cortical circuits [7–10]. In particular, there is evidence for reduced basal ganglia volumes , a volume decrease of the amygdala in adults [11, 12], but increased volumes in children , and an increase of gray matter volumes in the mesencephalon [13, 14] and in dorsolateral prefrontal regions in children, but not in adults . In a treatment-naïve boys-only group without comorbidities, increased volumes of the putamen bilaterally and the corpus callosum (subregion 3) were found . A study using diffusion tensor imaging (DTI), a method that allows conclusions about the microstructural organization based on water diffusion properties , provided additional evidence for white matter abnormalities of somatosensory pathways in GTS adults . By means of high-resolution structural MRI, recent studies showed cortical thinning in large areas of the frontal and parietal lobe in children with GTS , and reduced cortical thickness in motor, premotor, prefrontal and lateral orbitofrontal areas in adult patients suffering from GTS . Available morphometric studies strongly suggest that structural patterns in children are quite opposite to those in adults indicating the occurrence of neuroplastic developmental processes during the course of the disease. In line with this assumption are findings of increased prefrontal volumes with associated decreased size of the corpus callosum in GTS children [20, 21] - which are thought to reflect compensatory mechanisms in order to facilitate suppression of tics [9, 22] - but decreased dorsal prefrontal and increased corpus callosum volumes in GTS adults which are possibly associated with symptom persistence into adulthood [9, 21, 23]. In a recent study from our group, we used voxel-based morphometry (VBM) and magnetization transfer imaging (MTI) to investigate actually unmedicated adult GTS "only" patients and found structural differences predominantly in prefrontal areas, stressing a more fronto-striatal dysfunction rather than a distinct basal ganglia involvement .
VBM has been proven to be a powerful method for the in vivo study of human brain structures [25, 26]. This technique relies on the segmentation of magnetic resonance (MR) images into different tissue types (e.g. gray matter, white matter, and cerebrospinal fluid) using probability measures based on image intensities . It is a semi-automated, unbiased technique that is based on a voxel-wise analysis without the need for a priori hypotheses. Here we sought to address the question of gray matter abnormalities in adult GTS patients with comorbid OCD and/or ADHD compared to healthy controls using VBM. More specifically, we applied a sophisticated computational image analysis approach both to compare regional volumes of gray matter throughout the brain  and to test whether there is a common pattern of structural brain alteration occurring in patients with GTS plus OCD as well as in those with comorbid ADHD.
Demographical and clinical characteristics
GTS plus (n = 8)
GTS- OCD (n = 17)
GTS-ADHD (n = 4)
Healthy control group (n = 24)
Mean 30.7 (9), range 18-49
Mean 30.6 (10.9), range 18-59
ADHD symptom list part 1
ADHD symptom list part 2
Differences in GM volumes between patients with GTS and healthy control subjects
Regional gray matter volume differences in patients suffering from GTS compared to controls.
Tourette GM volume decrease compared to healthy controls
IFG (BA 47/12)
GM volume increase of GTS+ADHD and GTS+ADHD+OCD compared to GTS+OCD
In order to be sure that the IQ score differences between groups have not confounded our results, we have conducted a separate analysis including IQ scores as covariates. We still found a cluster of reduced gray matter volume density in the left IFG. Thus, we are sure that the significant, but small IQ group differences cannot explain differences of gray matter volumes between groups.
Differences in GM volumes between GTS patient subgroups
In order to show that GTS subgroups with ADHD comorbidity (n = 8 + 4) are significantly different compared to the GTS group without ADHD comorbidity (GTS and OCD; n = 17) in regard to gray matter volumes, we directly compared these groups. By comparing the subgroups with comorbid ADHD (GTS + ADHD and GTS "plus") with patients suffering from Tourette with OCD symptomatology only (GTS + OCD), we found an increase of gray matter density in the left amygdala. This cluster was also significant in comparison to healthy controls, indicating differences due to pathology. We found no significant clusters of volume reductions here.
GM volumes: correlations with clinical scores
Brain regions showing significant correlations with clinical scores
GM correlations with RVTRS
Posterior cingulate cortex
GM correlations with Y-BOCS (total score)
Superior parietal lobule
GM correlations with ADHD scores (Symptom checklist, CAARS, WURS-K)
GM correlations with BDI
Anterior cingulate cortex
Middle temporal gyrus
Lateral occipitotemporal gyrus
GM correlations with STAI
Anterior cingulate cortex
Middle occipital gyrus
Lateral occipitotemporal gyrus
Middle frontal gyrus
Superior parietal lobule
Medial frontal gyrus
Tic severity measured with the RVTRS correlated negatively with the volume of the right superior frontal gyrus (r = -0.65) and the left insula (r = -0.63). No regions showed a positive correlation with the RVTRS.
The left postcentral gyrus showed a negative correlation with the Y-BOCS scores assessing obsessions (r = -0.63) and compulsions (r = -0.69) in patients with GTS. No regions showed a positive correlation with the Y-BOCS.
By conducting multiple regression analyses including ADHD scales (symptom checklist inattention and hyperactivity, CAARS, WURS-K), we found a positive correlation with gray matter volumes of the left (inattention: r = 0.5; hyperactivity: r = 0.7) and right putamen (inattention: r = 0.6; hyperactivity: r = 0.63) while no negative correlations could be observed.
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 .
By means of VBM we found a gray matter reduction in the left IFG in GTS patients with comorbid OCD/ADHD compared to healthy controls. Furthermore, the volume of the left amygdala was found to be increased in the subgroup of GTS patients with ADHD symptomatology. From our data it is suggested that the coexistence of tics and ADHD and/or OCD represents an additive model, since in patients with GTS "plus" severity of tics, ADHD, and OCD each correlated with those brain regions (left insula and the right superior frontal cortex, putamen, left postcentral gyrus, respectively) that are also involved in "pure" GTS, "pure" ADHD and "pure" OCD.
Forty-one adult (≥ 18 years) male patients with the diagnosis of GTS according to DSM IV-TR criteria were scanned for this study. All patients suffered either from comorbid OCD, ADHD, or both. All patients were actually unmedicated for at least six months before entering the study. For the diagnosis of ADHD we used both, a psychiatric examination and different self-rating scales including the DSM-IV symptom check-list for ADHD  consisting of 18 screening questions for inattention and hyperactivity (9 questions each), the Conners' Adult ADHD Rating Scales (CAARS; Self report - long version) , consisting of 66 items assessing for inattention/memory problems, impulsivity/emotional lability, hyperactivity/restlessness, and problems with self-concept, and the Wender-Utah-Rating-Scale short form (WURS-K) , a 25-item-self-rating for the retrospective diagnosis of ADHD in adults. To diagnose and rate OCD, we used a psychiatric evaluation as well as the German versions of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) , a measurement for OCD containing a checklist for specific obsessions and compulsions as well as a rating scale separately for obsessions and compulsions (scoring for expenditure of time, interference, distress, resistance, degree of control). Tic severity was rated using the Yale Global Tic Severity Scale (YGTSS) , consisting of ratings separately for motor and vocal tics concerning number, frequency, intensity, complexity, and interference, plus an overall TS impairment rating as well as the modified Rush Video-based Tic Rating Scale (RVTRS) . The RVTRS is based on a 10-minute film protocol including near and far body views rating on five disability categories (number of body areas, frequency of motor tics, frequency of vocal tics, severity of motor tics, and severity of vocal tics). In addition, IQ was assessed with the MWT-B (Mehrfachwahl-Wortschatz-Intelligenztest), a test in which a real word among four pseudo-words has to be identified . In order to assess depression and anxiety, Beck Depression Inventory-II (BDI), consisting of 21 questions about the subject's feeling in the last week) , and STAI (State-Trait Anxiety Inventory), consisting of 40 questions for measuring both "state anxiety" and "trait anxiety" in adults  were used.
None of the patients had a history of head trauma, epilepsy, brain surgery, systemic illness, drug or alcohol abuse, or any other significant comorbid disorder. In all patients a neurological and psychiatric examination was performed by one of the authors (KR MV) who is experienced in the diagnosis of TS, OCD, and ADHD. Twenty-five healthy control subjects individually matched for age and gender were enrolled in this study. Exclusion criteria were the same as for the patients' group. Healthy controls were interviewed and examined in the same way as patients. Handedness for all participants was assessed with the Edinburgh Handedness Inventory . The study was approved by the local ethical standards committee and was carried out in accordance with the declaration of Helsinki. All participants gave written informed consent after all procedures had been fully explained to them before entering the study.
Of 66 participants included in the study, data sets of 53 (n = 29 GTS patients, n = 24 healthy controls) participants were used for further analyses. Data sets of 13 participants did not survive our strict image quality control due to different reason: poor image quality due to excessive movement artifacts (n = 9 GTS patients), anatomical abnormalities that prevent reliable and accurate spatial normalization (n = 1 healthy control), and claustrophobia leading to incomplete measurements (n = 3 GTS patients). Demographic and clinical parameters are summarized in Table 1. For further analyses patients were divided into three different subgroups according to their kind and number of comorbid disorders: (1) GTS "plus" (with comorbid OCD and ADHD, n = 8), (2) GTS-OCD (n = 17), and (3) GTS-ADHD (n = 4).
MR image acquisition
All MRI scans were obtained at 1.5 Tesla General Electric Signa Horizon LX (General Electric Company, Milwaukee, WI, USA). A high-resolution three-dimensional T1-weighted spoiled gradient recalled echo (SPGR) sequence generated 124 contiguous sagittal slices (TR = 24 ms; TE = 8 ms; flip angle = 30°; voxel dimensions 0.97 × 0.97 × 1.5 mm3).
Voxel-based GM volume analysis
Data were processed and examined using the SPM8 software (Wellcome Department of Imaging Neuroscience Group, London, UK; http://www.fil.ion.ac.uk/spm, where we applied VBM standard routines and default parameters implemented in the VBM8 toolbox (r347) http://dbm.neuro.uni-jena.de/vbm.html running under the MATLAB 7.10 (R2010a; Mathworks, Sherbon, Massachusetts) environment. Voxel-based morphometry is a whole-brain, unbiased, semi-automated technique for characterizing regional cerebral differences in structural magnetic resonance images . Before segmentation into gray and white matter segments, the anterior commissure was manually defined. Images were then normalized, bias field corrected, and tissue classified. Subsequently, analyses were performed on GM segments resulted in the DARTEL (Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra) analysis, which were multiplied by the non-linear components derived from the normalization matrix in order to preserve actual GM values locally. This procedure allows for comparing the absolute amount of tissue corrected for individual brain sizes. The rationale behind DARTEL is to increase the accuracy of inter-subject alignment by modeling the shape of each brain using millions of parameters (three parameters for each voxel). This procedure has been shown to improve the parameterization of brain shapes . Images were smoothed with an 8 mm full-width at half-maximum (FWHM) isotropic Gaussian kernel to make the data more normally distributed and to compensate for the inexact nature of spatial normalization. By applying independent t-tests we examined differences of demographic data and clinical variables between patients suffering from GTS and healthy controls. An ANOVA was conducted to calculate voxel-wise GM differences. To avoid possible edge effects between different tissue types, we excluded all voxels with values of less than 0.1 (absolute threshold masking). Correlations of gray matter parameter estimates of patients with clinical scores were calculated using multiple regression models in SPM8. Statistical outcomes were corrected for multiple comparisons using an empirically determined extent threshold at an uncorrected p < 0.001. This method is implemented in SPM8 and refers to the estimated smoothness of the images. After determining of the number of resels, the expected Euler characteristic is calculated. This is used to give the correct threshold (number of voxels) that is required to control for false positive results.
Resulting parameter estimates were extracted from significant clusters and scaled to the global mean with the REX toolbox http://web.mit.edu/swg/software.htm.
This study was kindly supported by a grant of the Tourette syndrome Association, Inc., New York, USA.
We thank all participants for their support and their willingness to be part of this study, as well as five anonymous reviewers for helpful comments.
- Jankovic J: Tourette's syndrome. N Engl J Med. 2001, 345 (16): 1184-1192. 10.1056/NEJMra010032.PubMedView ArticleGoogle Scholar
- Robertson MM: Tourette syndrome, associated conditions and the complexities of treatment. Brain. 2000, 123 (Pt 3): 425-462.PubMedView ArticleGoogle Scholar
- Singer HS: Tourette's syndrome: from behaviour to biology. Lancet Neurol. 2005, 4 (3): 149-159.PubMedView ArticleGoogle Scholar
- Freeman RD, Fast DK, Burd L, Kerbeshian J, Robertson MM, Sandor P: An international perspective on Tourette syndrome: selected findings from 3,500 individuals in 22 countries. Dev Med Child Neurol. 2000, 42 (7): 436-447. 10.1017/S0012162200000839.PubMedView ArticleGoogle Scholar
- Khalifa N, von Knorring AL: Psychopathology in a Swedish population of school children with tic disorders. J Am Acad Child Adolesc Psychiatry. 2006, 45 (11): 1346-1353. 10.1097/01.chi.0000251210.98749.83.PubMedView ArticleGoogle Scholar
- Albin RL, Mink JW: Recent advances in Tourette syndrome research. Trends Neurosci. 2006, 29 (3): 175-182. 10.1016/j.tins.2006.01.001.PubMedView ArticleGoogle Scholar
- Gerard E, Peterson BS: Developmental processes and brain imaging studies in Tourette syndrome. J Psychosom Res. 2003, 55 (1): 13-22. 10.1016/S0022-3999(02)00581-0.PubMedView ArticleGoogle Scholar
- Ludolph AG, Juengling FD, Libal G, Ludolph AC, Fegert JM, Kassubek J: Grey-matter abnormalities in boys with Tourette syndrome: magnetic resonance imaging study using optimised voxel-based morphometry. Br J Psychiatry. 2006, 188: 484-485. 10.1192/bjp.bp.105.008813.PubMedView ArticleGoogle Scholar
- Peterson BS, Staib L, Scahill L, Zhang H, Anderson C, Leckman JF, Cohen DJ, Gore JC, Albert J, Webster R: Regional brain and ventricular volumes in Tourette syndrome. Arch Gen Psychiatry. 2001, 58 (5): 427-440. 10.1001/archpsyc.58.5.427.PubMedView ArticleGoogle Scholar
- Peterson BS, Thomas P, Kane MJ, Scahill L, Zhang H, Bronen R, King RA, Leckman JF, Staib L: Basal Ganglia volumes in patients with Gilles de la Tourette syndrome. Arch Gen Psychiatry. 2003, 60 (4): 415-424. 10.1001/archpsyc.60.4.415.PubMedView ArticleGoogle Scholar
- Ludolph AG, Pinkhardt EH, Tebartz van Elst L, Libal G, Ludolph AC, Fegert JM, Kassubek J: Are amygdalar volume alterations in children with Tourette syndrome due to ADHD comorbidity?. Dev Med Child Neurol. 2008, 50 (7): 524-529. 10.1111/j.1469-8749.2008.03014.x.PubMedView ArticleGoogle Scholar
- Peterson BS, Choi HA, Hao X, Amat JA, Zhu H, Whiteman R, Liu J, Xu D, Bansal R: Morphologic features of the amygdala and hippocampus in children and adults with Tourette syndrome. Arch Gen Psychiatry. 2007, 64 (11): 1281-1291. 10.1001/archpsyc.64.11.1281.PubMed CentralPubMedView ArticleGoogle Scholar
- Devinsky O: Neuroanatomy of Gilles de la Tourette's syndrome. Possible midbrain involvement. Arch Neurol. 1983, 40 (8): 508-514. 10.1001/archneur.1983.04210070048013.PubMedView ArticleGoogle Scholar
- Garraux G, Goldfine A, Bohlhalter S, Lerner A, Hanakawa T, Hallett M: Increased midbrain gray matter in Tourette's syndrome. Ann Neurol. 2006, 59 (2): 381-385. 10.1002/ana.20765.PubMedView ArticleGoogle Scholar
- Roessner V, Overlack S, Schmidt-Samoa C, Baudewig J, Dechent P, Rothenberger A, Helms G: Increased putamen and callosal motor subregion in treatment-naive boya with Tourette syndrome indictaes changes in the bihemispheric motor network. J Child Psychol Psychiatry. 2011, 52 (3): 306-314. 10.1111/j.1469-7610.2010.02324.x.PubMedView ArticleGoogle Scholar
- Johansen-Berg H, Behrens TE: Just pretty pictures? What diffusion tractography can add in clinical neuroscience. Curr Opin Neurol. 2006, 19 (4): 379-385. 10.1097/01.wco.0000236618.82086.01.PubMed CentralPubMedView ArticleGoogle Scholar
- Thomalla G, Siebner HR, Jonas M, Baumer T, Biermann-Ruben K, Hummel F, Gerloff C, Muller-Vahl K, Schnitzler A, Orth M, et al: Structural changes in the somatosensory system correlate with tic severity in Gilles de la Tourette syndrome. Brain. 2009, 132 (Pt 3): 765-777.PubMedView ArticleGoogle Scholar
- Sowell ER, Kan E, Yoshii J, Thompson PM, Bansal R, Xu D, Toga AW, Peterson BS: Thinning of sensorimotor cortices in children with Tourette syndrome. Nat Neurosci. 2008, 11 (6): 637-639. 10.1038/nn.2121.PubMed CentralPubMedView ArticleGoogle Scholar
- Worbe Y, Gerardin E, Hartmann A, Valabregue R, Chupin M, Tremblay L, Vidailhet M, Colliot O, Lehericy S: Distinct structural changes underpin clinical phenotypes in patients with Gilles de la Tourette syndrome. Brain. 2010, 133 (Pt 12): 3649-3660.PubMedView ArticleGoogle Scholar
- Plessen KJ, Gruner R, Lundervold A, Hirsch JG, Xu D, Bansal R, Hammar A, Lundervold AJ, Wentzel-Larsen T, Lie SA, et al: Reduced white matter connectivity in the corpus callosum of children with Tourette syndrome. J Child Psychol Psychiatry. 2006, 47 (10): 1013-1022. 10.1111/j.1469-7610.2006.01639.x.PubMed CentralPubMedView ArticleGoogle Scholar
- Plessen KJ, Wentzel-Larsen T, Hugdahl K, Feineigle P, Klein J, Staib LH, Leckman JF, Bansal R, Peterson BS: Altered interhemispheric connectivity in individuals with Tourette's disorder. Am J Psychiatry. 2004, 161 (11): 2028-2037. 10.1176/appi.ajp.161.11.2028.PubMedView ArticleGoogle Scholar
- Spessot AL, Plessen KJ, Peterson BS: Neuroimaging of developmental psychopathologies: the importance of self-regulatory and neuroplastic processes in adolescence. Ann N Y Acad Sci. 2004, 1021: 86-104. 10.1196/annals.1308.010.PubMedView ArticleGoogle Scholar
- Margolis A, Donkervoort M, Kinsbourne M, Peterson BS: Interhemispheric connectivity and executive functioning in adults with Tourette syndrome. Neuropsychology. 2006, 20 (1): 66-76.PubMed CentralPubMedView ArticleGoogle Scholar
- Müller-Vahl KR, Kaufmann J, Grosskreutz J, Dengler R, Emrich HM, Peschel T: Prefrontal and anterior cingulate cortex abnormalities in Tourette Syndrome: evidence from voxel-based morphometry and magnetization transfer imaging. BMC Neurosci. 2009, 10: 47-10.1186/1471-2202-10-47.PubMed CentralPubMedView ArticleGoogle Scholar
- May A, Gaser C: Magnetic resonance-based morphometry: a window into structural plasticity of the brain. Curr Opin Neurol. 2006, 19 (4): 407-411. 10.1097/01.wco.0000236622.91495.21.PubMedView ArticleGoogle Scholar
- Whitwell JL: Voxel-based morphometry: an automated technique for assessing structural changes in the brain. J Neurosci. 2009, 29 (31): 9661-9664. 10.1523/JNEUROSCI.2160-09.2009.PubMedView ArticleGoogle Scholar
- Mietchen D, Gaser C: Computational morphometry for detecting changes in brain structure due to development, aging, learning, disease and evolution. Front Neuroinformatics. 2009, 3: 25.PubMed CentralView ArticleGoogle Scholar
- Ashburner J, Friston KJ: Voxel-based morphometry-the methods. NeuroImage. 2000, 11 (6 Pt 1): 805-821.PubMedView ArticleGoogle Scholar
- Peterson BS, Staib L, Scahill L, Zhang H, Anderson C, Leckman JF, Cohen DJ, Gore JC, Albert J, Webster R: Regional brain and ventricular volumes in Tourette syndrome. Arch Gen Psychiatry. 2001, 58 (5): 427-440. 10.1001/archpsyc.58.5.427.PubMedView ArticleGoogle Scholar
- Rotge JY, Guehl D, Dilharreguy B, Cuny E, Tignol J, Bioulac B, Allard M, Burbaud P, Aouizerate B: Provocation of obsessive-compulsive symptoms: a quantitative voxel-based meta-analysis of functional neuroimaging studies. J Psychiatry Neurosci. 2008, 33 (5): 405-412.PubMed CentralPubMedGoogle Scholar
- Corbetta M, Shulman GL: Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci. 2002, 3 (3): 201-215.PubMedView ArticleGoogle Scholar
- Rotge JY, Guehl D, Dilharreguy B, Tignol J, Bioulac B, Allard M, Burbaud P, Aouizerate B: Meta-analysis of brain volume changes in obsessive-compulsive disorder. Biol Psychiatry. 2009, 65 (1): 75-83. 10.1016/j.biopsych.2008.06.019.PubMedView ArticleGoogle Scholar
- van den Heuvel OA, Remijnse PL, Mataix-Cols D, Vrenken H, Groenewegen HJ, Uylings HB, van Balkom AJ, Veltman DJ: The major symptom dimensions of obsessive-compulsive disorder are mediated by partially distinct neural systems. Brain. 2009, 132 (Pt 4): 853-868.PubMedGoogle Scholar
- Rotge JY, Langbour N, Jaafari N, Guehl D, Bioulac B, Aouizerate B, Allard M, Burbaud P: Anatomical alterations and symptom-related functional activity in obsessive-compulsive disorder are correlated in the lateral orbitofrontal cortex. Biol Psychiatry. 2010, 67 (7): e37-e38. 10.1016/j.biopsych.2009.10.007.PubMedView ArticleGoogle Scholar
- Radua J, Mataix-Cols D: Voxel-wise meta-analysis of grey matter changes in obsessive-compulsive disorder. Br J Psychiatry. 2009, 195 (5): 393-402. 10.1192/bjp.bp.108.055046.PubMedView ArticleGoogle Scholar
- Jeffries KJ, Schooler C, Schoenbach C, Herscovitch P, Chase TN, Braun AR: The functional neuroanatomy of Tourette's syndrome: an FDG PET study III: functional coupling of regional cerebral metabolic rates. Neuropsychopharmacol. 2002, 27 (1): 92-104. 10.1016/S0893-133X(01)00428-6.View ArticleGoogle Scholar
- Leckman JF, Zhang H, Vitale A, Lahnin F, Lynch K, Bondi C, Kim YS, Peterson BS: Course of tic severity in Tourette syndrome: the first two decades. Pediatrics. 1998, 102 (1 Pt 1): 14-19.PubMedView ArticleGoogle Scholar
- Plessen KJ, Bansal R, Peterson BS: Imaging evidence for anatomical disturbances and neuroplastic compensation in persons with Tourette syndrome. J Psychosom Res. 2009, 67 (6): 559-573. 10.1016/j.jpsychores.2009.07.005.PubMed CentralPubMedView ArticleGoogle Scholar
- Perlov E, Philipsen A, Tebartz van Elst L, Ebert D, Henning J, Maier S, Bubl E, Hesslinger B: Hippocampus and amygdala morphology in adults with attention-deficit hyperactivity disorder. J Psychiatry Neurosci. 2008, 33 (6): 509-515.PubMed CentralPubMedGoogle Scholar
- Shaw P, Rabin C: New insights into attention-deficit/hyperactivity disorder using structural neuroimaging. Curr Psychiatry Rep. 2009, 11 (5): 393-398. 10.1007/s11920-009-0059-0.PubMedView ArticleGoogle Scholar
- Hutton C, Draganski B, Ashburner J, Weiskopf N: A comparison between voxel-based cortical thickness and voxel-based morphometry in normal aging. NeuroImage. 2009, 48 (2): 371-380. 10.1016/j.neuroimage.2009.06.043.PubMed CentralPubMedView ArticleGoogle Scholar
- Ridgway GR, Henley SM, Rohrer JD, Scahill RI, Warren JD, Fox NC: Ten simple rules for reporting voxel-based morphometry studies. NeuroImage. 2008, 40 (4): 1429-1435. 10.1016/j.neuroimage.2008.01.003.PubMedView ArticleGoogle Scholar
- Pell GS, Briellmann RS, Chan CH, Pardoe H, Abbott DF, Jackson GD: Selection of the control group for VBM analysis: influence of covariates, matching and sample size. NeuroImage. 2008, 41 (4): 1324-1335. 10.1016/j.neuroimage.2008.02.050.PubMedView ArticleGoogle Scholar
- Debes NM, Lange T, Jessen TL, Hjalgrim H, Skov L: Performance on Wechsler intelligence scales in children with Tourette syndrome. Eur J Paediatr Neurol. 2011, 15 (2): 146-154. 10.1016/j.ejpn.2010.07.007.PubMedView ArticleGoogle Scholar
- Westmoreland Corson P, Nopoulos P, Miller DD, Arndt S, Andreasen NC: Change in basal ganglia volume over 2 years in patients with schizophrenia: typical versus atypical neuroleptics. Am J Psychiatry. 1999, 156 (8): 1200-1204.Google Scholar
- Lang DJ, Kopala LC, Vandorpe RA, Rui Q, Smith GN, Goghari VM, Lapointe JS, Honer WG: Reduced basal ganglia volumes after switching to Olanzapine in chronically treated patients with schizophrenia. Am J Psychiatry. 2004, 161 (10): 1829-1836. 10.1176/appi.ajp.161.10.1829.PubMedView ArticleGoogle Scholar
- Fahim C, Yoon U, Sandor P, Frey K, Evans AC: Thinning of the motor-cingulate-insular cortices in siblings concordant for Tourette syndrome. Brain Topogr. 2009, 22 (3): 176-184. 10.1007/s10548-009-0105-6.PubMedView ArticleGoogle Scholar
- Lerner A, Bagic A, Boudreau EA, Hanakawa T, Pagan F, Mari Z, Bara-Jimenez W, Aksu M, Garraux G, Simmons JM, et al: Neuroimaging of neuronal circuits involved in tic generation in patients with Tourette syndrome. Neurol. 2007, 68 (23): 1979-1987. 10.1212/01.wnl.0000264417.18604.12.View ArticleGoogle Scholar
- Bohlhalter S, Goldfine A, Matteson S, Garraux G, Hanakawa T, Kansaku K, Wurzman R, Hallett M: Neural correlates of tic generation in Tourette syndrome: an event-related functional MRI study. Brain. 2006, 129 (Pt 8): 2029-2037.PubMedView ArticleGoogle Scholar
- Yu R, Mobbs D, Seymour B, Calder AJ: Insula and striatum mediate the default bias. J Neurosci. 2010, 30 (44): 14702-14707. 10.1523/JNEUROSCI.3772-10.2010.PubMedView ArticleGoogle Scholar
- Pourfar M, Feigin A, Tang CC, Carbon-Correll M, Bussa M, Budman C, Dhawan V, Eidelberg D: Abnormal metabolic brain networks in Tourette syndrome. Neurol. 2011, 76 (11): 944-952. 10.1212/WNL.0b013e3182104106.View ArticleGoogle Scholar
- Yoo SY, Roh MS, Choi JS, Kang DH, Ha TH, Lee JM, Kim IY, Kim SI, Kwon JS: Voxel-based morphometry study of gray matter abnormalities in obsessive-compulsive disorder. J Korean Med Sci. 2008, 23 (1): 24-30. 10.3346/jkms.2008.23.1.24.PubMed CentralPubMedView ArticleGoogle Scholar
- Nakao T, Nakagawa A, Nakatani E, Nabeyama M, Sanematsu H, Yoshiura T, Togao O, Tomita M, Masuda Y, Yoshioka K, et al: Working memory dysfunction in obsessive-compulsive disorder: a neuropsychological and functional MRI study. J Psychiatr Res. 2009, 43 (8): 784-791. 10.1016/j.jpsychires.2008.10.013.PubMedView ArticleGoogle Scholar
- Seidman LJ, Valera EM, Makris N: Structural brain imaging of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005, 57 (11): 1263-1272. 10.1016/j.biopsych.2004.11.019.PubMedView ArticleGoogle Scholar
- Mataix-Cols D, Wooderson S, Lawrence N, Brammer MJ, Speckens A, Phillips ML: Distinct neural correlates of washing, checking, and hoarding symptom dimensions in obsessive-compulsive disorder. Arch Gen Psychiatry. 2004, 61 (6): 564-576. 10.1001/archpsyc.61.6.564.PubMedView ArticleGoogle Scholar
- Cath DC, Spinhoven P, Hoogduin CA, Landman AD, van Woerkom TC, van de Wetering BJ, Roos RA, Rooijmans HG: Repetitive behaviors in Tourette's syndrome and OCD with and without tics: what are the differences?. Psychiatry Res. 2001, 101 (2): 171-185. 10.1016/S0165-1781(01)00219-0.PubMedView ArticleGoogle Scholar
- Ellison-Wright I, Ellison-Wright Z, Bullmore E: Structural brain change in attention deficit hyperactivity disorder identified by meta-analysis. BMC Psychiatry. 2008, 8: 51-10.1186/1471-244X-8-51.PubMed CentralPubMedView ArticleGoogle Scholar
- Sobel LJ, Bansal R, Maia TV, Sanchez J, Mazzone L, Durkin K, Liu J, Hao X, Ivanov I, Miller A, et al: Basal ganglia surface morphology and the effects of stimulant medications in youth with attention deficit hyperactivity disorder. Am J Psychiatry. 2010, 167 (8): 977-986. 10.1176/appi.ajp.2010.09091259.PubMed CentralPubMedView ArticleGoogle Scholar
- Almeida Montes LG, Ricardo-Garcell J, Barajas De La Torre LB, Prado Alcantara H, Martinez Garcia RB, Fernandez-Bouzas A, Avila Acosta D: Clinical correlations of grey matter reductions in the caudate nucleus of adults with attention deficit hyperactivity disorder. J Psychiatry Neurosci. 2010, 35 (4): 238-246. 10.1503/jpn.090099.PubMedView ArticleGoogle Scholar
- Roessner V, Becker A, Banaschewski T, Rothenberger A: Psychopathological profile in children with chronic tic disorder and co-existing ADHD: additive effects. J Abnorm Child Psychol. 2007, 35 (1): 79-85. 10.1007/s10802-006-9086-z.PubMedView ArticleGoogle Scholar
- Sass H, Wittchen HU, Zaudig M, Houben I: Diagnostisches und Statistisches Manual Psychischer Störungen -Textrevision- DSM-IV-TR. 2003, Bern: Hans HuberGoogle Scholar
- Conners CK: Clinical use of rating scales in diagnosis and treatment of attention-deficit/hyperactivity disorder. Pediatr Clin North Am. 1999, 46 (5): 857-870. 10.1016/S0031-3955(05)70159-0. viPubMedView ArticleGoogle Scholar
- Retz-Junginger P, Retz W, Blocher D, Stieglitz RD, Georg T, Supprian T, Wender PH, Rosler M: [Reliability and validity of the Wender-Utah-Rating-Scale short form. Retrospective assessment of symptoms for attention deficit/hyperactivity disorder]. Nervenarzt. 2003, 74 (11): 987-993. 10.1007/s00115-002-1447-4.PubMedView ArticleGoogle Scholar
- Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, Heninger GR, Charney DS: The yale-brown obsessive compulsive scale. I. Development, use, and reliability. Arch Gen Psychiatry. 1989, 46 (11): 1006-1011. 10.1001/archpsyc.1989.01810110048007.PubMedView ArticleGoogle Scholar
- Leckman JF, Riddle MA, Hardin MT, Ort SI, Swartz KL, Stevenson J, Cohen DJ: The yale global tic severity scale: initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry. 1989, 28 (4): 566-573. 10.1097/00004583-198907000-00015.PubMedView ArticleGoogle Scholar
- Goetz CG, Pappert EJ, Louis ED, Raman R, Leurgans S: Advantages of a modified scoring method for the rush video-based tic rating scale. Mov Disord. 1999, 14 (3): 502-506. 10.1002/1531-8257(199905)14:3<502::AID-MDS1020>3.0.CO;2-G.PubMedView ArticleGoogle Scholar
- Lehrl S: Mehrfachwahl-Wortschatz-Intelligenztest MWT-B. 2005, unveränderte Aufl. Balingen: Spitta Verlag, 5.Google Scholar
- Hautzinger M, Keller F, Kühner C: BDI-II Beck-Depressions-Inventar Revision. 2009, Auflage. Frankfurt: Pearson Assessment, 2.Google Scholar
- Spielberger CD, Gorsuch R, Lushene R, Vagg P, Jacobs G: Manual for the State-Trait Anxiety Inventory. 1983, Palo Alto: Consulting Psychologists Press, IncGoogle Scholar
- Oldfield RC: The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia. 1971, 9 (1): 97-113. 10.1016/0028-3932(71)90067-4.PubMedView ArticleGoogle Scholar
- Ashburner J: A fast diffeomorphic image registration algorithm. NeuroImage. 2007, 38 (1): 95-113. 10.1016/j.neuroimage.2007.07.007.PubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.