Functional neuroanatomy of tics.

CHAPTER TWO

Functional Neuroanatomy of Tics Irene Neuner*,†,{,1, Frank Schneider†,{, N. Jon Shah*,{,}

*Institute of Neuroscience and Medicine 4, INM4, Forschungszentrum Ju¨lich GmBH, Juelich, Germany † Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany { JARA—Translational Brain Medicine, Germany } Department of Neurology, RWTH Aachen University, Aachen, Germany 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Structural Abnormalities 2.1 Cortex 2.2 White matter 2.3 Caudate nucleus, globus pallidum, and putamen 2.4 Amygdala and hippocampus 2.5 Thalamic nuclei 2.6 Cerebellum 3. Functional Findings 3.1 Transcranial magnetic stimulation 3.2 Functional neuroimaging—15O-PET/18FDG-PET 3.3 Functional neuroimaging—fMRI 4. Tics—A Matter of Connectivity? Acknowledgments References

36 37 37 39 40 41 41 42 42 42 61 62 64 66 66

Abstract The therapeutic success of haloperidol in the treatment of Tourette syndrome (TS) put an end to the discussion about a “hysteric” or “neurotic” origin of TS. The cortico-striatothalamo-cortical circuit has been identified as an underlying neurobiological correlate of TS. In this review we explore the main findings of structural alterations in TS including cortical areas, basal ganglia, hippocampus, amygdala, midbrain, and cerebellum. Based on the structural changes we examine the functional pattern described by the findings of fMRI and 15O-PET/18FDG PET investigations. From the neuroimaging findings a cortical origin of the generation of tics is indicated. Future research on the neuronal footprint of TS should be directed towards addressing the question of which patterns of connectivity distinguish individuals in whom tics disappear during early adulthood from those in whom the tics persist. The understanding of this pathomechanism could provide a key on how to influence dysconnectivity in TS, for example, by more specific pharmaceutical intervention or by individually adopted EEG and/or fMRI neurofeedback.

International Review of Neurobiology, Volume 112 ISSN 0074-7742 http://dx.doi.org/10.1016/B978-0-12-411546-0.00002-0

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2013 Elsevier Inc. All rights reserved.

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Irene Neuner et al.

1. INTRODUCTION The therapeutic success of Shapiro and others in treating tics with the D2-antagonist haloperidol puts an end to the discussion about a “hysteric” or “neurotic” origin of tics in Tourette syndrome (TS) and laid the ground for the search of its neurobiological correlates (Shapiro, Shapiro, & Wayne, 1973). Since the most prominent symptoms of TS are tics, it is often classified as a movement disorder. Basal ganglia are a common candidate structure for the neuronal correlate of movement disorders such as Parkinson’s disease or dystonia. Therefore, early investigations in TS focused on the basal ganglia. Nevertheless, clinical experience demonstrates that the basal ganglia solely cannot be the underlying neurobiological correlate of TS. Oliver Sacks and a colleague describe in their report about shadowing a man who suffers from Tourette syndrome and acts despite the tics as a surgeon and flies small airplanes in his free time. This documentary demonstrates various clinical hallmarks of TS (http://oliversacks.tripod.com/ sur.html). Tics wax and wane, and they are reduced by processes that require full attention (piloting, performing surgery) and increase in frequency when the concentration of the individual is interrupted. Emotions also interact with the tics. If a TS patient is tense, awaiting/afraid of being teased, the frequency of the tics explodes; this also occurs in moments of very positive emotions such as marriage (Cavanna & Termine, 2012; Neuner & Ludolph, 2011; Robertson, 2012). Oliver Sacks also describes in the report that at the beginning of the meeting with the patient, he was very “controlled” and showed few tics, in contrast to the last period of the visit in which they were familiar with each other and therefore the patient showed more tics, “feeling free to tic.” Such modulations imply that the basal ganglia need to interact closely with the cortex and with the limbic system (Alexander, Crutcher, & DeLong, 1990; Alexander, DeLong, & Strick, 1986; Draganski et al., 2008). Thus, the cortico-striato-thalamo-cortical circuit with its different loops has been discussed as the neuronal correlate underlying tics (see Fig. 2.1, taken with permission from Singer (2005)). Several structures within the loops summarized by Alexander and coworkers as the “motor,” “oculomotor,” “dorsolateral prefrontal,” “lateral-orbitofrontal,” and “limbic” loops of the cortico-striato-thalamo-cortical circuit have been reported as altered in TS patients (Draganski et al., 2010).

Neuroanatomy of Tics

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Figure 2.1 Pathophysiology of Tourette syndrome. Structures of the cortico-striatothalamo-cortical circuit. DA, dopamine; ENK, enkephalins; Glu, glutamate; GPe, globus pallidus externus; GPi, globus pallidus internus; LC, locus coeruleus; MR, median raphe; NE, norepinephrine; S, serotonin; SNpc, substantia nigra pars compacta; SNpr, substantia nigra pars reticulata; SUBP, substance P; STN, subthalamic nucleus; VTA, ventral tegmental area. Taken with permission from Singer (2005).

2. STRUCTURAL ABNORMALITIES 2.1. Cortex There is significant evidence of cortical alterations in TS (Felling & Singer, 2011; Plessen, Bansal, & Peterson, 2009). Thinning of the prefrontal cortex was described in children with TS in a magnetic resonance imaging

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(MRI)-based cortical thickness analysis (Sowell et al., 2008). Cortical thickness correlated negatively with tic severity indicating a mutual deficit in the inhibition of tics by the prefrontal cortex. This was also replicated in a study by Fahim and coworkers (Fahim et al., 2010). Fahim and colleagues reported in 34 adolescents with TS (mean age 17.2 years) significant cortical thinning in the frontoparietal and somatosensory cortices. Gender also affected the cortical thickness. The frontal-parietal cortices were thinner in boys in comparison to girls with TS. Furthermore, a significant involvement in the frontoparietal cortex was observed with age (Fahim et al., 2010). Draganski and colleagues took the analysis a step further and combined different MR-based imaging techniques. They included T1-weigthed scans as basis for voxel-based morphometry (VBM) and cortical thickness analysis as well as a diffusion-weighted acquisition for diffusion tensor imaging (DTI) allowing for the analysis of white matter (Draganski et al., 2010). In a comparison of 40 adult Tourette patients versus 40 healthy controls, Tourette individuals showed a relative reduction of gray matter volume in orbitofrontal, ventrolateral prefrontal cortices, and the anterior cingulate cortex. Importantly, as a “pure” TS is with a 10% rate rather the exception than the rule, the presence of comorbidities and symptom severity modulated the degree of gray matter alterations (Draganski et al., 2010). The reduction in cortical thickness and its negative correlation with severity of the tics supports the results obtained by Sowell and colleagues in children with TS (Sowell et al., 2008). They report volume increases in the primary somatosensory cortex depending on the intensity of “urges,” the premonitory sensations often preceding a motor tic. The results obtained by Draganski and colleagues (Draganski et al., 2010) match the VBM findings of Mueller-Vahl and colleagues reported in a sample of adult male Tourette patients. These encompassed decreased gray matter in prefrontal cortex, sensorimotor cortex, and anterior cingulate cortex (Mu¨ller-Vahl et al., 2009). Worbe and colleagues also found in a MRI study, by the means of cortical thickness analyses, different phenotypes in TS depending on the structural neuronal alterations (Worbe et al., 2010). A pattern of cortical thinning in primary motor regions was found mostly in patients with simple tics. In patients with simple and complex tics, cortical thinning extended into prefrontal and parietal regions was found. For the Tourette patient group with comorbid obsessive-compulsive disorder Worbe and colleagues report a trend for reduced cortical thickness in the anterior cingulate cortex and the hippocampus. Although the majority of MR-based studies report alterations in Tourette patients in comparison to healthy controls, there are also reports


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in the literature describing no changes. One example is a study by Roessner and coworkers in drug-naı¨ve boys with “pure” TS (Roessner et al., 2009), in which a VBM whole-brain analysis approach for data acquired at 1.5 T showed no significant differences. However, no region of interest approach was applied (Roessner et al., 2009) and in a slightly larger cohort (48 vs. 39, children aged 9/10–15 years all male, no comorbidities, no medication), alterations in the putamen (increased volume) and callosal motor subregion (larger) were reported (Roessner et al., 2011). An increased volume of the putamen in 14 boys with TS was described in a prior VBM study by Ludolph and colleagues (Ludolph et al., 2006). MR-based results are complemented by postmortem investigations. In a postmortem study in three TS individuals, a marked increase in density of prefrontal D2-receptor protein was described, suggesting the presence of a prefrontal-dopaminergic abnormality in TS (Minzer, Lee, Hong, & Singer, 2004).

2.2. White matter The severity of motor tics and premonitory urges in the adult cohort assessed by Draganski and colleagues (Draganski et al., 2010) corresponded to alterations in the white matter integrity of the corticocortico and cortico-subcortical connections. Noteworthy are in this respect the changes in the corpus callosum, frontostriatal, and motor pathways, which correspond well to another DTI study in an adult sample (Neuner, Kellermann, et al., 2010). With focus on white matter DTI studies, it was reported that white matter integrity in the corticospinal tract and the anterior limb of the internal capsule in adult Tourette patients is reduced (Neuner, Kellermann, et al., 2010). A potential hint on the pathophysiology is the reduction in fractional anisotropy in the corpus callosum (see Fig. 2.2), indicative of impaired white matter integrity based on altered myelination as indicated by the increased radial diffusivity. A myelination deficit has been discussed as a result of genetic alterations in TS patients in the predescribed and controversially discussed SLITRK1 (Abelson et al., 2005; Miranda et al., 2009; Scharf et al., 2008; Stillman et al., 2009), whose role has been investigated in a large sample of families (Karagiannidis et al., 2012). Thomalla and colleagues report in an adult patient sample without medication and comorbidities alterations of the underlying white matter under the supplementary motor area (SMA), the pre- and postcentral gyrus, and the ventral-posterolateral nucleus of the right thalamus (Thomalla et al., 2009).

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Figure 2.2 Diffusion imaging in Tourette patients. Upper line: Red indicates significant differences in fractional anisotropy as a potential marker of white matter integrity in Tourette patients versus healthy controls. Lower line: Blue indicates significant differences in radial diffusivity as a potential marker of myelination in Tourette patients versus healthy controls. Taken with permission from Neuner et al. (2011).

Of particular importance in the pathophysiology of Tourette is the altered interhemispheric cross talk via the corpus callosum. MR-based investigations by Peterson, Draganski, and Neuner described marked alterations in the corpus callosum in adults (Draganski et al., 2010; Neuner, Kellermann, et al., 2010; Peterson et al., 1993), Plessen, Roessner, and Cavanna report modifications of the corpus callosum in Tourette children (Cavanna et al., 2010; Plessen et al., 2004, 2007; Roessner et al., 2012). Interestingly, in a monozygotic twin pair discordant for TS, the only difference (lower FA in the affected twin) was found by DTI precisely in the corpus callosum (Cavanna et al., 2010).

2.3. Caudate nucleus, globus pallidum, and putamen Peterson and colleagues presented in a study including 154 TS individuals a reduced volume of the caudate nucleus in children and suggested it as a potential trait marker for TS (Peterson et al., 2003). Noteworthy in this


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respect is the exclusion of individuals having received prior neuroleptic medication from the analysis. In a smaller sample of 43 children, Bloch and colleagues identified the caudate volume in children with TS as a predictor of the severity of tics and obsessive–compulsive behavior in early adulthood (Bloch, Leckman, Zhu, & Peterson, 2005). In adult and children TS patients with comorbid OCD, the lenticular nucleus also appeared to be smaller in VBM analyses. Based on DTI, microstructural alterations were reported in the thalamus of TS children (Makki, Behen, Bhatt, Wilson, & Chugani, 2008), whereas in adults, diffusivity parameters of the basal ganglia correlated with symptom severity (Neuner et al., 2011).

2.4. Amygdala and hippocampus A cross-sectional MRI study in 154 patients with TS aged 6–63 years showed larger volumes of the hippocampus and the amygdala in patients in comparison to controls (Peterson et al., 2007). The difference was driven by changes of the head and medial surface of the hippocampus and the dorsal and ventral surfaces of the amygdala (over its basolateral and central nuclei). These structural changes are in line with functional alterations which show a marked amygdala hypersensitivity and altered connectivity of the amygdala in adult TS patients (Neuner, Kupriyanova, et al., 2010; Werner, Stoecker, Kellermann, Wegener, et al., 2011). In a smaller group (n ¼ 17) of boys with TS, smaller volumes of the amygdala were detected (Ludolph et al., 2008). Since these volume changes did not correlate with tic severity but with ADHD symptom severity the question was raised whether the ADHD comorbidity and not TS itself is driving these alterations (Ludolph et al., 2008).

2.5. Thalamic nuclei In a large sample (154 TS individuals, aged 6–63 years), an MRI study performed by the Peterson group showed an enlargement (5%) of the thalamus mainly over the lateral portion (Miller et al., 2010). Post hoc testing did not reveal confounding effects by IQ, comorbid disorders, or medication. This report strengthens the findings of an enlarged left thalamus by Lee and colleagues in a smaller sample (n ¼ 18) of treatment-naı¨ve boys with TS (Lee et al., 2006). Within the thalamic nuclei lie different target points for the insertion of deep brain stimulation electrodes (Ackermans, Kuhn, Neuner, Temel, & Visser-Vandewalle, 2013; Neuner et al., 2009).

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2.6. Cerebellum From the large Peterson data set (TS individuals n ¼ 163), Tobe and colleagues reported marked alterations in the cerebellum (Tobe et al., 2010). Both cerebellar hemispheres showed a marked reduction in volume which resulted from reduced gray matter in Crus I, lobules VI, VIIB, and VIIIA. These regional changes correlated positively with increasing tic symptom severity and motor disinhibition. These findings, mainly from MRI, show that all constituting parts of the cortico-striato-thalamo-cortical circuit exhibit alterations in TS. However, all these structural changes are derived from cross-sectional studies, and it remains unclear which alterations in these regions are the primary pathophysiological correlate of TS and which changes are the result of neuroplasticity. The question is also whether such changes always imply an alteration in function or connectivity. Only studies with a high sample size in a longitudinal design would be able to address these questions adequately. A comprehensive review of structural alterations in TS is presented in Table 2.1 (Plessen et al., 2009).

3. FUNCTIONAL FINDINGS Donald Cohen summarized the pathophysiology of TS as a lack of inhibition affecting impulses, movements, thoughts, attention, and behavior (Cohen & Leckman, 1991). Table 2.2 gives an overview of the different functional studies focusing on motor tasks, tics, or activation during cognitive tasks assessed by 15O-PET/18FDG PET, fMRI, and MEG.

3.1. Transcranial magnetic stimulation A noninvasive tool for the investigation of inhibition on a motor level is transcranial magnetic stimulation (TMS). Heise and colleagues reported that “short interval intracortical inhibition was reduced in the early phase of movement preparation (similar to rest) followed by a transition toward more inhibition” (Heise et al., 2010). Heise and colleagues discuss this as a compensatory mechanism where the motor cortex acts as a “relay station,” that is, increasing inhibitory activation and thereby downregulation of neuronal excitability. Thus, when performing a challenging motor task, such as piano playing, the abnormal high neuronal excitability at rest in Tourette patients normalizes during the movement execution due to the increasing inhibitory signals which arise from the motor cortex. In a behavioral study driven by

Table 2.1 Main findings of the anatomical MRI studies (n ¼ 27) in persons with TS for various brain regions: (a) subcortical, (b) corpus callosum, (c) cortex, (d) limbic regions, and (e) whole-brain analyses Area of Correction for Age Controls; age References interest brain size Diagnosis Male/female (mean SD) (mean SD) Method Main findings (a) Subcortical regions

Peterson et al. (1993)

BG

Brain size index

TS (n ¼ 14)

11/3

31.8 years (8.5)

Singer et al. (1993)

BG

Area of the five largest intracranial slices slice thickness

TS (n ¼ 19); TS þ ADHD (n ¼ 18)

14/4; 15/3

VOI n ¼ 18; 11.8 years (range 7–16); 9.8 years (range 6–15) 11.1 years (range 9–13)

Boys with TS showed trend toward a left smaller putamen (P < 0.08)

Hyde et al. (1995)

BG

Total brain volume

10 monozygotic 16/4 twin pairs with TS

16.3 years (range 9–31)

No controls VOI

Caudate nucleus volumes # in the more severely affected twin (6%; P < 0.01)

Castellanos, Giedd, Hamburger, Marsh, & Rapoport (1996)

BG and anterior frontal region

Total brain volume

TS þ ADHD (n ¼ 14); ADHD (26)

10.4 years (1.9); 10.7 years (1.9)

n ¼ 31; 10.9 years (1.9)

Rightward asymmetry of putamen reversed in the ADHD and TS þ ADHD group (P < 0.009)

14/0; 26/0

n ¼ 14; 32.4 VOI years (8.8)

VOI

Volume of the left lenticular nucleus # (P < 0.25) in TS

Continued

Table 2.1 Main findings of the anatomical MRI studies (n ¼ 27) in persons with TS for various brain regions: (a) subcortical, (b) corpus callosum, (c) cortex, (d) limbic regions, and (e) whole-brain analyses—cont'd Area of Correction for Age Controls; age References interest brain size Diagnosis Male/female (mean SD) (mean SD) Method Main findings

Zimmerman, BG and ventricles Abrams, Giuliano, Denckla, & Singer (2000)

Area of the five largest intracranial slices slice thickness

TS (n ¼ 19)

0/19


VOI n ¼ 21; 10.7 years (range 8–15)

No robust differences between girls with TS and controls

Peterson et al. BG (2003)

WBV

TS (n ¼ 154)

115/39


VOI n ¼ 130; 21.0 years (range 6–63)

Caudate nucleus # in the TS group, independent of age (P ¼ 0.01); lenticular nucleus # in TS adults (P < 0.02)

Amat et al. (2006)

Not relevant

TS (n ¼ 62); ADHD (n ¼ 45); OCD (n ¼ 28)

78/22

11.4 years (2,6)

n ¼ 32; 10.0 years (1.7)

Higher proportion of subcortical hyperintensities in children with neuropsychiatric disorders (OR ¼ 6.9), no difference with respect to cerebral hyperintensities

BG, cortex, cerebellum

Radiological evaluation of proton density and T2-weighted images; brain regions determined by VOI

Lee et al. (2006)

Thalamus

WBV

TS (n ¼ 18); comorbidity any Axis 1 exclusion criteria

18/0

9.3 years (2.3);

n ¼ 16; 10.0 years (1.8)

VOI

Left thalamus " in TS (P ¼ 0.002); group difference in overall brain size (P ¼ 0.013) and in IQ (P ¼ 0.019)

Wang et al. (2007)

BG and thalamus

Total cerebral TS (n ¼ 13); volumes and chronic tic transformation disorder (n ¼ 2)

10/5

33.4 years (11.0)

n ¼ 15; 33.1 years (11.6)

VOI of the BG, large deformation highdimensional brain mapping

No significant group differences in volume or shape of the BG (caudate, putamen, globus pallidus) and the thalamus

Makki et al. (2008)

BG and thalamus

DTI/VBM

TS (n ¼ 23)

19/4

11.8 years (3.3)

n ¼ 35; 13.1 years (3.2)

DTI and VOI tracing and VBM

Decreased anisotropy right thalamus (P ¼ 0.025) and increased water diffusivity bilaterally putamen (P ¼ 0.027); left caudate volume # (P ¼ 0.011) and bilateral thalamus volume # (left P ¼ 0.011); right P ¼ 0.006) Continued

Table 2.1 Main findings of the anatomical MRI studies (n ¼ 27) in persons with TS for various brain regions: (a) subcortical, (b) corpus callosum, (c) cortex, (d) limbic regions, and (e) whole-brain analyses—cont'd Area of Correction for Age Controls; age References interest brain size Diagnosis Male/female (mean SD) (mean SD) Method Main findings (b) Cortex

Peterson et al. Cortical (2011) regions, ventricles

WBV

TS (n ¼ 155)

114/41

18.7 years (13.4)

n ¼ 131; 20.8 years (13.4)

Parcellation of cerebral subdivisions

TS subjects dorsal prefrontal volumes " (P < 0.0004) and parieto-occipital regions (P < 0.002), but inferior occipital volumes # (P < 0.03)

n ¼ 26; 10.6 years (2.7)

Semiautomated normalization into Talairach space

TS larger proportion of white matter in the right frontal lobe (P < 0.01), ADHD reduced frontal volume (P < 0.05)

n ¼ 13; 9.9 years 10.0 years (1.1); 9.4 years (1.2) (1.5)

Frontal subparcellation protocol determining gray and white matter

Decrease of deep white matter in the left frontal lobe in TS (P ¼ 0.02)

Fredericksen et al. (2002)

Frontal Total frontal volume, volume white/gray matter composition

11/0; 14/0; 10.7 years TS (n ¼ 11); 12/0 (2.2); TS þ ADHD 11.7 years (n ¼ 14); (2.4); ADHD (n ¼ 12) 10.6 years (1.7)

Kates et al. (2002)

Four frontal WBV regions, deep white matter

13/0; 13/0 TS (n ¼ 13); ADHD (n ¼ 13)

TS (n ¼ 19)

19/0

9.7 years (2.7) n ¼ 17; 9.8 years (1.9)

Cortical thickness

Coregistration TS (n ¼ 25)

18/7


Cortical pattern Cortical thinning n ¼ 35; matching in frontal and 12.3 years parietal lobes in (range 7–21) TS; thinning in sensorimotor regions correlated positively with tic symptoms

BG, cortex, cerebellum

Not relevant

78/22

11.4 years (2,6)

n ¼ 32; 10.0 years (1.7)

Hong et al. (2002)

Cerebral and Total brain cerebellar volume volume

Sowell et al. (2008)

Amat et al. (2006)

TS (n ¼ 62); ADHD (n ¼ 45); OCD (n ¼ 28)

Semiautomated stereotacticbased parcellation method

Radiological evaluation of Proton density and T2-weighted images; brain regions determined by VOI

TS had larger frontal lobe white matter (P ¼ 0.038), smaller right (3.3%) and larger left frontal lobe gray matter (3.3%)

Higher proportion of subcortical hyperintensities in children with neuropsychiatric disorders (OR ¼ 6.9), no difference with respect to cerebral hyperintensities Continued


18/0 TS (n ¼ 18); comorbidity any Axis 1 exclusion criteria

Lee et al. (2006)

Thalamus

WBV

Wang et al. (2007)

BG and thalamus

Total cerebral TS (n ¼ 13); volumes and chronic tic transformation disorder (n ¼ 2)

Makki et al. (2008)

BG and thalamus

DTI/VBM

TS (n ¼ 23)

9.3 years (2.3) n ¼ 16; 10.0 years (1.8)

VOI

Left thalamus " in TS (P ¼ 0.002); group difference in overall brain size (P ¼ 0.013) and in IQ (P ¼ 0.019)

10/5

33.4 years (11.0)

n ¼ 15; 33.1 years (11.6)

VOI of the BG, large deformation highdimensional brain mapping

No significant group differences in volume or shape of the BG (caudate, putamen, globus pallidus) and the thalamus

19/4

11.8 years (3.3)

n ¼ 35; 13.1 years (3.2)

DTI and VOI tracing and VBM

Decreased anisotropy right thalamus (P ¼ 0.025) and increased water diffusivity bilaterally putamen (P ¼ 0.027); Left caudate volume # (P ¼ 0.011) and bilateral thalamus volume # (left P ¼ 0.011; right P ¼ 0.006)

(c) CC

Peterson et al. CC (1994)

Midsagittal head area

TS (n ¼ 14)

31.8 years (8.5)

n ¼ 14; 32.4 years (8.8)

ROI

CC reduced by 18% in the TS group (P < 0.006)

Baumgardner CC et al. (1996)

Intracranial area

13/3; 19/2; 12.6 years TS (n ¼ 16); 13/0 (2.2); TS þ ADHD 11.2 years (n ¼ 21); (1.6); ADHD (n ¼ 13) 11.3 years (1.4)

n ¼ 27; 10.8 years (2.6)

ROI

Compared with HCs, the rostral body of the callosum was 17% " in the TS group (P ¼ 0.007); TS þ ADHD: intermediate CC size; Pure ADHD: # CC (P ¼ 0.004)

Moriarty et al. CC and BG (1997)

Brain size index

TS (n ¼ 17)

11/6

35.0 years n ¼ 8; (range 17–62) 33.0 years (range 20–45)

ROI þ VOI

TS group had " CC and loss of asymmetry in caudate nucleus

WBV

TS children (n ¼ 97); TS adults (n ¼ 43)

77/20

11.2 years (2.3)

Presence and size of CSP rated on an ordinal scale

TS predictor for CSP grade, # CSP (P < 0.03 in children; P < 0.05 in adults); # CSP was correlated

Kim & Peterson (2003)

CSP

11/3

n ¼ 17; 9.8 years (1.9)

Continued


with higher ADHD symptom severity for inattention (P < 0.002) and hyperactivity/ impulsivity (P < 0.003) in the TS group Plessen et al. (2004)

CC

WBV

TS (n ¼ 158)

117/41

18.5 years (13.3)

n ¼ 121; 19.7 years (12.6)

ROI

CC # in the TS group (P < 0.005); interaction with age: TS children having # CCs and TS adults " CCs

Plessen et al. (2006)

CC

DTI local measurement

TS (n ¼ 20)

20/0

13.6 years (1.9)

n ¼ 20; 13.4 years (2.4)

DTI analysis of CC subdivisions

TS decreased FA values in all subdivisions of the CC (P < 0.009)

TS (n ¼ 154)

115/39

18.7 years (13.4)

n ¼ 128; 20.2 years (13.2)

VOI and surface matching analyses

Overall volumes amygdala and hippocampus " in TS group (P ¼ 0.006)

(d) Limbic regions

Peterson et al. Amygdala WBV and (2007) and coregistration hippocampus

Ludolph et al. (2008)

Amygdala

WBV

TS (n ¼ 17)

17/0

11.7 years (2.0);

n ¼ 17; 12.6 years (2.1)

VOI

Proportion of the left sided amygdale/whole brain # in TS group (P ¼ 0.03), correlated inversely with DSM-IV ADHD criteria (P ¼ 0.027)

(e) Whole-brain analyses

Ludolph et al. (2006)

Whole brain with focus on BG

Normalized to TS (n ¼ 14) VBM template (children)

14/0

12.5 years

n ¼ 15; 13.4 years

VBM

Locally " gray matter volumes bilaterally ventral putamen and decreases left hippocampal gyrus (P < 0.001)

Garraux et al. (2006)

Whole brain with focus on midbrain and BG

Normalized to TS (n ¼ 31) VBM template

25/7

32.0 years (10.5)

n ¼ 31; 32.0 years (11.0)

VBM

Locally " in left midbrain gray matter volume (FDR corrected P ¼ 0.03)

Martino et al. (2008)

Whole brain with focus onG

Normalized to TS, Antibasal ganglia VBM antibodies template (ABGA)þ (n ¼ 9): TS ABGA (n ¼ 13)

4/5; 7/6

34.3 years (11.4); 29.5 years (14.2)

No controls VBM and DTI No differences in morphometry or (voxel-based water diffusivity in FA maps) adult patients with TS that were ABGAþor ABGA Continued


Thomalla et al. (2009)

Whole brain with focus on white matter


13/2

34.5 years (8.9)

n ¼ 15; 34.6 years (9.1)

Mu¨ller-Vahl et al. (2009)

Whole brain


19/0

30.4 years n ¼ 20; (range 18–60) 31.7 years (range 18–65)

Makki, Govindan, Wilson, Behen, & Chuganie (2009)

Whole brain Normalized to TS (n ¼ 18) with focus on MNI template frontostriatal images connections

14/4

11.3 years (2.4)

n ¼ 20; 12.2 years (4.1)

VBM in DTI

Bilateral FA in WM post-and precentral gyrus, left supplementary motor area and right thalamus; inverse correlation with tic severity

VBM and MTI Locally # gray matter volumes prefrontal areas, the anterior cingulate gyrus; white matter # right inferior frontal gyrus, left superior frontal gyrus, anterior CC Whole-brain analyses with fiber tracking

Connections between caudate nucleus and anteriordorsolateral cortex #

", increased volume; #, decreased volume; ADHD, attention-deficit/hyperactivity disorder; BG, basal ganglia; CC, corpus callosum; CSP, cavum septi pellucidi; CT, chronic tic disorder; DLPF, dorsolateral prefrontal; DTI, diffusion tensor imaging; FDR, false discovery rate; HC, healthy control; MNI, Montreal Neurological Institute; MTI, magnetization transfer imaging; ROI, region of interest measurements; TS, Tourette syndrome; VBM, voxel-based morphometry; VOI, volume of interest measurement; WBV, whole-brain volume; WM, white matter.

Table 2.2 Summary of findings from functional neuroimaging studies in Tourette individuals Cohort characteristics: Number, gender, age, Method of medication, comorbidities References investigation Paradigm/analysis approach

Main results

Braun et al. (1993)

18

FDG-PET

Patients instructed to let tic occur freely

N ¼ 16 adult TS (2f, 14m, aged 33 7 years), medication free, comorbidities NA versus 16 healthy controls

Decreased metabolic activity in paralimbic and prefrontal cortices, nucleus accumbens, ventromedial caudate, midbrain, increased metabolic activity in SMA, lateral premotor, Rolandic cortices

Braun et al. (1995)

18

FDG-PET

Patients instructed to let tic occur freely

N ¼ 18 adult TS (2f, 16m, aged 33 7 years), medication free, comorbidities assessed

Complex behavioral symptoms such as OCD, impulsivity, coprolalia, selfinflictions behavior correlate with increased metabolic activity in the orbitofrontal cortices

Biswal et al. (1997)

fMRI at 1.5T

Finger tapping

N ¼ 5 adult TS (1f, 4m, aged 26.6 11.4 years), medication free, comorbidities NS versus 5 healthy controls

Activation of sensorimotor cortices and SMA larger in TS than in controls

Eidelberg et al. (1997)

18

No specific instruction described

N ¼ 10 adult TS (5f/5m), 41.5 12.7 years, medication free, comorbidities NA versus 10 healthy controls

Increased activity in lateral premotor, SMA, and midbrain; decreased activity in caudate nucleus, thalamus, putamen, globus pallidus, and hippocampus

FDG-PET

Continued

Table 2.2 Summary of findings from functional neuroimaging studies in Tourette individuals—cont'd Cohort characteristics: Number, gender, age, Method of medication, comorbidities investigation Paradigm/analysis approach References

Main results

Peterson et al. (1998)

fMRI at 1.5T

Block design, instruction to inhibit tics and let tics go freely in 40 s block; no monitoring of performance

N ¼ 22 adult TS (11f, 11m, aged 35.7 10.9 years), 15 medication free, 10 OCD, 3 ADHD as child not as adult

Contrast nonsuppressed versus suppressed showed a reduction of signal intensity in the basal ganglia and thalamus and increased activation in the midfrontal, middle and superior temporal gyrus, anterior cingulate cortex, and inferior occipital cortices

Stern et al. (2000)

15

O-PET

Instructions to let tics occur freely, video-controlled approach

N ¼ 6 adult TS (0f, 6m, aged 36.7 10.9 years), 4 medicated, including comorbidities

Activated structures included: medial and lateral premotor cortices, primary motor cortex, dorsolateral prefrontal cortex, inferior parietal cortex, superior temporal gyrus, Broca‘s area, anterior cingulate cortex, putamen, thalamus, insula, claustrum

Jeffries et al. (2002)

18

FDG-PET

Connectivity analysis

N ¼ 18 adult TS (2f/16m, 33 7 years), medication free, 11OCD, ADHD NA versus 16 healthy controls

Altered patterns of connectivity for the ventral striatum, primary motor areas, somatosensory association areas, and the insula

Bohlhalter et al. (2006)

fMRI at 1.5T

Instruction to let tics occur freely; analysis of tics 2 s prior to tics and at tic occurrence; authors report video monitoring from outside but no details are given how in this setup the upper part of the body and the head lying in the coil is covered

N ¼ 10 adult TS (6f, 4m, aged 31 11 years), 9 medication free, 4 OCD, 2 ADHD

Two seconds before tic occurrence: SMA, parietal operculum, insular cortex, anterior cingulate cortex activated at tic onset: sensorimotor areas including superior parietal lobule bilaterally, dorsolateral prefrontal cortex, parietal operculum, SMA, insula, putamen, vermis, and substantia nigra

Lerner et al. (2007)

15

O-PET

Instructions to let tics occur freely

N ¼ 9 adult TS (2f, 7m, aged 20–44 years), medication free, 7 OCD, 5 ADHD, 1 obsessive–compulsive personality disorder versus 9 matched control healthy subjects

Activity in the cerebellum, thalamus, insula, putamen, caudate, pre- and postcentral gyrus, SMA, anterior cingulate cortex

Baym, Corbett, Wright, & Bunge (2008)

fMRI at 3T

Cognitive task “Nemo task,” task switching between categories color and direction

N ¼ 18 children TS (3f, 15m, aged 35.7 10.9 years), 16 medication free, comorbidities NS, actual scores for OCD and ADHD measures included as covariates in fMRI analysis

Higher tic severity was associated with slower task performance behaviorally; neuroimaging: (a) tic severity was correlated with stronger activity of the nucleus subthalamicus and ventral tegmental area; (b) tic severity Continued

Table 2.2 Summary of findings from functional neuroimaging studies in Tourette individuals—cont'd Cohort characteristics: Method of Number, gender, age, References investigation Paradigm/analysis approach medication, comorbidities

Main results

versus 19 matched healthy volunteers

was positively correlated with activation in the striatum, globus pallidus internus, thalamus, motor cortex; (c) tic severity correlated positively with activity in the nucleus accumbens; elevated mesolimbic activity as function of tic severity specifically during performance of most cognitively challenging trials

Hampson, Tokoglu, King, Constable, & Leckman (2009)

fMRI at 3T

Instructions to allow tics to occur freely; ROI based approach SMA; correlational analysis of coactivated voxels with SMA during tics; shift of analysis window with regard to tic onset

N ¼ 16 adult TS/CTD (3f, 13m, aged 30 9.7 years), 8 medication free, 2 OCD, 2 ADHD and major depressive disorder versus 10 healthy controls

Increased functional interaction between M1 and SMA as a pathophysiological marker for TS; alterations present during preparation and execution of voluntary movements indicating increased motor-cortical interaction in TS

Marsh, Maia, & Peterson (2009)

fMRI at 1.5T

Stroop interference task

N ¼ 32 TS children (5f, 27m, aged 12.82 2.8 years),

Larger frontostriatal activation was associated with

9 medication free, 10 OCD, 6 ADHD, 4 OCD/ADHD versus 20 matched healthy controls, 34 adult TS individuals (14f, 20m, aged 35.27 11.1 years), 21 medication free, 15 OCD, 2 ADHD, OCD/ADHD 1, versus 50 matched healthy controls

poorer performance, reduced default-mode processing in ventral prefrontal and posterior cingulate cortices

Kawohl, Bruehl, Krowatschek, Ketteler, and Herwig (2009)

fMRI at 3T

Tic suppression

One male, 28 years, no medication, comorbidities NS

Anterior cingulate cortex activated during tic suppression

Church et al. (2009)

fMRI at 1.5T

Connectivity analysis, graph theory approach does not include basal ganglia as a hub

N ¼ 33 children TS (8f, 25m, aged 12.7 0.76), 22 on medication, 17 with comorbidities versus 42 healthy controls

Two control networks: frontoparietal network governing rapid adaptive online control, cinguloopercular network governing set maintenance; adolescents with TS have immature pattern, particularly in the frontoparietal network, aberrant connections

Mazzone et al. (2010)

fMRI at 1.5T

Inhibition and disinhibition of “semi”- involuntary eye blinks, block design, 40 s; member of study team

N ¼ 22 children TS (3f, 19m, aged 13.1 2.6, 1 medication free, 21 OCD, 11 ADHD, 4 OCD/ADHD) versus

During blink inhibition, TS individuals showed stronger activation in the frontal cortex and the striatum. Continued


Werner, Sto¨cker, Kellermann, Bath, et al. (2011) and Werner, Stoecker, Kellermann, Wegener, et al. (2011)

fMRI at 1.5T

Main results

observes blink performance via mirror in the MR suite

21 matched healthy controls, N ¼ 29 adult TS (12f, 17m, aged 35.1 11.1, medication free, OCD, ADHD, OCD/ADHD NS versus 48 matched healthy controls

Age effect: activation level in the dorsolateral and inferolateral prefrontal cortex and caudate nucleus increased with increasing age

Finger tapping, right, left, both hands, block design, video controlled

N ¼ 19 adult TS (6f, 13m, aged 34.3 10.9 years), 10 medication free, 2 OCD, 2 OCD/ADHD versus 18 matched healthy control subjects

Same behavioral output achieved by additional neuronal, activation; tapping dominant right hand shows increased activation in the midbrain and cerebellum; indication of failing deactivation of parts of default brain network; subgenual ACC fails to modulate with increasing task difficulty, altered functional connectivity of higher order motor networks in TS

Wang et al. (2012)

fMRI at 1.5T

Spontaneous versus imitated tics ICA analysis, Granger causality

N ¼ 13 adult TS (11f, 11m, aged 33.5 13.3 years), 7 medication free, 6 OCD, 2 ADHD, versus 21 matched healthy control subjects

Stronger pattern of activation in TS patients in the sensorimotor cortex, putamen, pallidum, and substantia nigra, positive correlation with tic severity; comparison “original tics” versus imitated tics: stronger activation in posterior parietal cortices

Roessner et al. (2012)

fMRI at 1.5T

Finger tapping right dominant hand, block design

N ¼ 19 boys TS, aged 12.5 1.4, medication free, no comorbidities versus 16 matched healthy controls

Decreased activation in the left premotor cortex and caudate nucleus while increased activation in the medial prefrontal gyrus

Franzkowiak et al. (2012)

MEG

Self-paced finger tapping

N ¼ 10 adult TS (2f, 8m, aged 35.7 3.1 years), 10 medication free, comorbidities excluded versus 10 healthy control subjects

Increased M1 activation in TS due to increased functional interaction between SMA and M1

Neuner et al. (2013)

fMRI at 1.5T

Instructions to allow tics to occur freely, videocontrolled with

N ¼ 16 adult TS (5f, 11m, aged 32.2 11.2 years), 6 medication free, 4 OCD, 2 ADHD

2 s prior to tic occurrence: SMA, primary motor cortex, primary somatosensory cortex, parietal operculum 1 s Continued


MR-compatible camera system (Neuner et al., 2007)

Main results

prior to tic occurrence: anterior cingulate, putamen, insula, amygdala, cerebellum, extrastriatal-visual cortex at tic occurrence: thalamus, primary motor and somatosensory cortices, central operculum activated

TS, Tourette syndrome; OCD, obsessive–compulsive disorder; ADHD, attention-deficit hyperactivity disorder; PET, positron emission tomography; fMRI, functional magnetic resonance imaging; MEG, magnetoencephalography; FDG, fluorodeoxyglucose; SMA, supplementary motor area; NA, not assessed; NS, not specified; CTD, chronic tic disorder.


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Neuner and coworkers, it was shown that the fine motor skills in Tourette patients are altered depending on the given task (Neuner et al., 2012) and in an fMRI finger-tapping study that the same motor performance in TS individuals is reached activating additional neuronal structures (Werner, Sto¨cker, Kellermann, Bath, et al., 2011).

3.2. Functional neuroimaging—15O-PET/18FDG-PET A controversial question is where the primary site of tic generation within the cortico-striato-thalamo-cortical circuit lies. Several functional studies applying fMRI and 15O-PET/18FDG-PET propose different candidates to answer this question (Biswal et al., 1997; Rickards, 2009). The first 18FDG-PET study by Braun and colleagues assessed 16 nonmedicated adult patients (Braun et al., 1993). They reported a decrease of metabolic activity in paralimbic and prefrontal cortices, particularly in orbitofrontal, insular, and parahippocampal cortices. Additional decreases were observed in the nucleus accumbens/ventromedial caudate and midbrain. An increase in glucose consumption was detected in the supplementary motor, lateral premotor, and Rolandic cortices. Increased metabolic activity of the orbitofrontal cortices was detected regarding complex behavioral symptoms such as obsessions and compulsions, impulsivity, coprolalia, and self-injurious behavior (Braun et al., 1995). By the means of 18FDGPET, Eidelberg and colleagues also identified in adult Tourette patients two distinct patterns separating TS individuals from controls (Eidelberg et al., 1997). One pattern was characterized by increased activity in lateral premotor, supplementary motor association cortices, and in the midbrain. The other pattern consisted of decreased activity in the nucleus caudate, thalamus, putamen, globus pallidus, and hippocampus. Lerner and colleagues investigated, by the means of 15O-PET, 9 adult Tourette patients during rest (with the instruction to release their tics, not to suppress them). They identified the following structures as active during “release”: cerebellum, thalamus, insula, putamen, caudate, pre/ postcentral gyrus, SMA, and anterior cingulate cortex (Lerner et al., 2007). Stern and colleagues also assessed tics simultaneously with a videocontrolled approach during 15O-PET (Stern et al., 2000). In this study the following structures were active during tics: cortex: medial and lateral premotor cortices, primary motor cortex, dorsolateral prefrontal cortex, inferior parietal cortex, superior temporal gyrus, Broca’s area; subcortical: ACC, nucleus caudate, putamen, thalamus, insula, claustrum.

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3.3. Functional neuroimaging—fMRI Peterson and colleagues investigated the neurobiological substrate of tics by the means of fMRI (Peterson et al., 1998). They instructed the patients to tic freely for 40 s followed by 40 s period of suppression. The study did not include a measure to control whether the patients were able to follow this strict and challenging instruction. The contrast nonsuppressed versus suppressed tics showed a marked reduction of signal intensity in the basal ganglia and thalamus as well as increased cortical activation in the midfrontal, middle and superior temporal gyrus, the ACC, and inferior occipital cortices (Peterson et al., 1998). Bohlhalter and colleagues performed an fMRI study in Tourette patients in order to assess the time line of events before and during tic occurrence (Bohlhalter et al., 2006). They detected the following pattern 2 s before tic onset: SMA, parietal operculum, insular cortex, and anterior cingulate were active; at tic onset the following pattern emerged: sensorimotor areas including superior parietal lobule bilaterally, dorsolateral prefrontal cortex, parietal operculum, SMA, insula, putamen, vermis, and substantia nigra. A similar pattern evolved in the fMRI study by Wang and colleagues (Wang et al., 2012) investigating spontaneous and simulated tics in TS individuals. For data analysis they used independent component analysis with hierarchical partner matching and Granger causality to investigate causal interactions between the identified activated regions. In summary they revealed a pattern of stronger neural activity and interregional causality in TS patients in comparison to healthy controls in all sections of the motor pathway including the sensorimotor cortex, putamen, pallidum, and substantia nigra. The activation in these key motor regions correlated positively with the severity of tics. The comparison of “original tics” versus voluntarily imitated tics showed a stronger activation in the posterior parietal cortices, putamen, and amygdala/hippocampus complex indicating an involvement of limbic structures in the generation of tics. A video-controlled fMRI study in adult Tourette patients (Neuner et al., 2007, 2013) assessed in 1s frames the neuronal activation 2 second before a tic, 1 second before a tic, and at tic onset. Tourette patients were instructed to let their tics go and not to suppress them during fMRI acquisition. For tic-related activity, the following structures exhibited activation. (see Fig. 2.3, taken from Neuner et al. (2013)): 2 s before a tic SMA, primary motor cortex, primary sensorimotor cortex, and parietal operculum were active. One second before a tic, the anterior cingulate, the putamen, the


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insula, the amygdala, the cerebellum, and the extrastriatal-visual cortex were active. With tic onset, the thalamus, primary motor and somatosensory cortices, and the central operculum were active. Noteworthy is that the place of tic generation seems to be the SMA, not, for example, within the thalamic nuclei or the globus pallidus internus which are frequently and successfully used as target structures for deep brain stimulation in TS. These results match the ones obtained by Hampson and colleagues in an fMRI study in 16 adult subjects analyzing time courses in the SMA and coactivated brain regions by the means of a correlational approach (Hampson et al., 2009). Electrical stimulation of the SMA is known in humans to trigger motor responses or anticipation that a movement is going to occur (Fried et al., 1991). As reported earlier, SMA has also been reported in early PET studies to show an increased metabolism of FDG in Tourette individuals. Next to the analysis of the underlying neuronal pattern of tics, fMRI studies addressed the question whether the neuronal pattern of voluntary movements is altered in Tourette individuals. The first investigation of Biswal and colleagues in 1997, a finger-tapping task, showed a larger activation in M1 and SMA in TS in comparison to healthy controls (Biswal et al., 1997). Jackson and colleagues reported in a study in 10 young TS children that patients exhibit enhanced control over their motor output, despite the involved high intermanual conflict, by applying a behavioral motor task-switching paradigm. The same individuals underwent DTI and the alterations in the corpus callosum and forceps minor predicted tic severity and enriched the structural findings with functional relevance ( Jackson et al., 2011). Roessner and colleagues studied the neurobiological substrate of finger tapping with the right dominant hand in an fMRI study including 19 treatment-naı¨ve boys without comorbidities (Roessner et al., 2012). TS patients differed from controls by a reduced activation in the left precentral gyrus and caudate nucleus while at the same time point the activation in the medial frontal gyrus was increased. This pattern is evident within the first years of tic onset, and therefore more likely to present a biomarker of TS per se rather than resulting from a compensatory mechanism of tics. Tackling the gray area of “semi-involuntary” movements, Mazzone and coworkers aimed at the investigation of eye blinking and its inhibition in Tourette individuals (19 children, 17 adults) versus age-matched healthy controls (Mazzone et al., 2010). They instructed the patients during an fMRI scan in a block design of 40 s to inhibit their eye blinks or to blink. During blink inhibition, TS individuals showed a stronger activation in the

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Figure 2.3 Activation pattern of the generation of tics 2 s before (left), 1 s before (middle), and at tic onset (right). Taken with permission from Neuner et al. (2013).

frontal cortex and the striatum. With increasing age the activation level in the dorsolateral and inferolateral prefrontal cortex and caudate nucleus increased in TS patients (Mazzone et al., 2010).

4. TICS—A MATTER OF CONNECTIVITY? The identification of structural and functional alterations in TS individuals points to the cortico-striato-thalamo-cortical neuronal framework, accompanied by a wide range of interactions between the main structures of the motor pathways with the limbic system and the prefrontal and


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orbitofrontal cortices. Makki and colleagues found, in a DTI study in 18 TS children aged between 7 and 17 years, a significantly lower probability of connection between the caudate nucleus and the anterior-dorsolateralfrontal cortex (Makki et al., 2009). The results of Marsh and coworkers are in line with the structural findings described earlier (Marsh et al., 2009). In this study, two collectives of TS individuals (32 children including medicated subjects and comorbidities; 34 adult individuals including medicated subjects and comorbidities) performed the Stroop inference task during fMRI acquisition. The analysis of the underlying neuronal pattern showed that larger activation in bilateral frontostriatal regions was associated with diminished performances in the patient group (Marsh et al., 2009). This reminds of patients’ reports according to which they are able to suppress their tics in a number of situations, for example, in the class room or lecture hall, but have trouble recalling the topic of the given lecture. This underscores the point one has to keep in mind that “brain regions do not operate in isolation” ( Jeffries et al., 2002). After the identification of the neuronal network beyond TS, the next step must be the analysis of connectivity within these circuits. Based on 18FDG-PET data analyzed with the focus on functional coupling, Jeffries and colleagues demonstrate that the connectivity of the ventral striatum was severely altered in TS individuals ( Jeffries et al., 2002). Changes in the coupling of other neuronal structures such as primary motor areas, somatosensory association areas, and the insula also distinguished TS individuals from healthy controls ( Jeffries et al., 2002). In an fMRI resting state study, Church and colleagues investigated “two of the brain’s tasks control networks—a frontoparietal network likely to be involved in more rapid, adaptive online control, and a cingulo-opercular network apparently important for set-maintenance” (Church et al., 2009). Church and colleagues reported that adolescents with TS showed immature patterns of connectivity, particularly the frontoparietal network that is discussed to maintain adaptive online control. Furthermore, additional aberrant connections were found in regions belonging to the frontoparietal network, possibly resulting in deficient inhibition—which may result in tic occurrence. Future neuroimaging studies need to disentangle, in a longitudinal design, the question of what distinguishes individuals in whom tics disappear during early adulthood from those in whom tics persist. Understanding this phenomenon will permit the identification and design of new therapeutic interventions such as a more specific pharmacotherapeutic approach or an EEG- and/or fMRI-driven individual neurofeedback.

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ACKNOWLEDGMENTS We thank all Tourette patients and their families for participating in our studies. We are grateful to the German Tourette Association and its members who supported our research by contributing with travel funds. We dedicate this paper to Ewald Flecken who passed away unexpectedly in April 2013. We thank Tony Sto¨cker, Thilo Kellermann, Hans Peter Wegener, Cornelius Werner, and Corinna Ehlen for their contributions to the Tourette imaging project. We thank Petra Engels, Barbara Elghahwagi, and Gabriele Oefler for their excellent technical assistance. The Institute of Neuroscience and Medicine (INM-4) acknowledges funding by the German Ministry for Education and Research (BMBF) and Siemens for the 9.4T project. Financial Disclosure. Irene Neuner reports no conflict of interest. Frank Schneider received compensation as a consultant for Janssen-Cilag, AstraZeneca, and Otsouka, manufacturers of antipsychotic medication. Frank Schneider received compensation for scientific talks or contribution in a prize jury by Janssen-Cilag, Wyeth, and AstraZeneca. Frank Schneider received funding for investigator initiated projects from AstraZeneca, Lilly, and Pfizer. N. Jon Shah reports funding from the BMBF and Siemens for the 9.4T MR/PET (magnetic resonance/positron emission tomography) project.

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A positive diagnosis of functional (psychogenic) tics.

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Functional neuroanatomy of intuitive physical inference.

Functional neuroanatomy of auditory scene analysis in Alzheimer's disease.

Functional neuroanatomy in panic disorder: Status quo of the research.

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Fatal attraction: TICs and MDSCs.

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Eye-movement tics in children.

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Functional neuroanatomy on the working memory under emotional distraction in patients with generalized anxiety disorder.

A Dual-Stream Neuroanatomy of Singing.

Paradoxical worsening of tics with haloperidol.