Neurobiology of Tourette Syndrome: Current Status and Need for Further Investigation

The Journal of Neuroscience, August 31, 2011 • 31(35):12387–12395 • 12387

Disease Focus

Editor’s Note: Disease Focus articles provide brief overviews of a neural disease or syndrome, emphasizing potential links to basic neural mechanisms. They are presented in the hope of helping researchers identify clinical implications of their research. For more information, see http://www.jneurosci.org/misc/ifa_minireviews.dtl.

Ryan J. Felling and Harvey S. Singer Department of Neurology, Division of Pediatric Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Tourette syndrome (TS) is a common, chronic neuropsychiatric disorder characterized by the presence of fluctuating motor and phonic tics. The typical age of onset is ϳ5–7 years, and the majority of children improve by their late teens or early adulthood. Affected individuals are at increased risk for the development of various comorbid conditions, such as obsessive–compulsive disorder, attention deficit hyperactivity disorder, school problems, depression, and anxiety. There is no cure for tics, and symptomatic therapy includes behavioralandpharmacologicalapproaches.EvidencesupportsTSbeinganinheriteddisorder;however,theprecisegeneticabnormality remains unknown. Pathologic involvement of cortico-striatal-thalamo-cortical (CSTC) pathways is supported by neurophysiological, brain imaging, and postmortem studies, but results are often confounded by small numbers, age differences, severity of symptoms, comorbidity, use of pharmacotherapy, and other factors. The primary site of abnormality remains controversial. Although numerous neurotransmitters participate in the transmission of messages through CSTC circuits, a dopaminergic dysfunction is considered a leading candidate. Several animal models have been used to study behaviors similar to tics as well as to pursue potential pathophysiological deficits. TS is a complex disorder with features overlapping a variety of scientific fields. Despite description of this syndrome in the late 19th century, there remain numerous unanswered neurobiological questions.

In the 1880’s, Georges Gilles de la tic disorders, to review current information or noises such as throat clearing, sniffing, or Tourette published a two-part article in on genetic and neurobiological mecha- grunting. In contrast, complex tics typically which he emphasized differences between nisms, and to identify areas in need of fur- involve more elaborate manifestations and tics and chorea. Although many of the de- ther investigation. appear to have a more purposeful action or scriptions about the disorder, which now verbalization. Examples of common com- bears his name [Tourette syndrome (TS)], The Clinical Problem plex tics are as follows: motor: touching ob- have been revised, his belief that tics are a The hallmark of TS is the presence of jects, clapping, obscene gestures, or body neurological movement disorder and not chronic, fluctuating motor and vocal tics. contortions; and phonic: the repetition of a psychiatric condition persists to the Best diagnosed by observation, tics are words including echolalia, palilalia, and present (Goetz and Klawans, 1982). Nev- sudden, repetitive, involuntary move- coprolalia. Characteristics that help to dif- ertheless, despite multiple advances and ments or vocalizations with differing ferentiate tics from other paroxysmal widespread acceptance of TS being a bio- degrees of intensity and frequency, and movement disorders include a waxing and logical disorder, the precise etiology and unpredictable durations (Kurlan, 2010). waning course, the presence of particular underlying pathophysiological mecha- Tics are currently classified as motor or factors that exacerbate (stress, anxiety, fa- nisms remain unknown. The goals of the vocal (phonic), although this separation tigue) or reduce (concentrating or focusing) present review are to briefly describe the has been questioned, and further subclas- symptoms, a suggestible nature, the pres- clinical phenomenology of TS and related sified into simple or complex categories. ence of a premonitory sensation, and brief Simple tics generally involve fewer muscle suppressibility. Received Jan. 10, 2011; revised June 7, 2011; accepted July 8, 2011. groups, are briefer in duration, and tend Tics are common in childhood, with CorrespondenceshouldbeaddressedtoDr.HarveyS.Singer,Divisionof to be more meaningless in their appear- epidemiological studies showing that ϳ20- Pediatric Neurology, Johns Hopkins Hospital, Rubenstein Child Health ance/phonation. Common examples of 30% of children exhibit brief, repetitive, Building,200NorthWolfeStreet,Suite2158,Baltimore,MD21287.E-mail: [email protected]. simple tics are as follows: motor: eye involuntary movements or sounds in a DOI:10.1523/JNEUROSCI.0150-11.2011 blinking, head jerking, facial grimacing, classroom setting (Kurlan et al., 2001). The Copyright © 2011 the authors 0270-6474/11/3112387-09$15.00/0 or shoulder shrugging; and phonic: sounds diagnosis of a tic disorder is based solely on 12388 • J. Neurosci., August 31, 2011 • 31(35):12387–12395 Felling and Singer • Disease Focus historical features and a clinical examina- also support a genetic disorder with a con- associated with a streptococcal infection tion that confirms their presence and elimi- cordance of chronic tics in 77–94% of (PANDAS). Indirect support of such a the- nates other etiological conditions. There is monozygotic compared to just 23% in dizy- ory includes a significantly higher incidence no reliable diagnostic test for TS or the spec- gotic twins (Price et al., 1985; Hyde et al., of autoimmune disease in the mothers of trum of disorders that have tics as their car- 1992). Despite these reports, the precise pat- children with tics (Murphy et al., 2010). dinal feature. The formal criteria for TS tern of transmission and the specific genes Nevertheless, the existence of this etiological require an age of onset before 18 years, the involved remain elusive. Linkage analy- entity is extremely controversial based on presence of multiple motor and at least one ses have suggested several chromosomal lo- both epidemiological and autoimmune vocal tic (not necessarily concurrently), a cations, but without a clear reproducible studies (Kurlan, 1998, 2004; Singer and Loi- waxing and waning course, the addition and locus (Pauls, 2006; O’Rourke et al., 2009). selle, 2003; Kurlan and Kaplan, 2004; Singer subtraction of various tics, the presence of Similarly, candidate gene studies have failed et al., 2005b; Kurlan et al., 2008; Singer et al., tic symptoms for at least 1 year, and the to yield consistent results for specific suscep- 2008; Morris et al., 2009; Leckman et al., absence of a precipitating illness (e.g., en- tibility genes. Much attention has been paid 2011). cephalitis, stroke, or degenerative disease) to dopaminergic candidates, and there is ev- or tic-inducing medication. Motor tics have idence of a significant association between Neurobiology of TS a typical age of onset of ϳ5–7 years, and the TS and a dopamine transporter polymor- Circuits course of TS can be quite variable. Most pa- phism (DAT1 Ddel) (Yoon et al., 2007b). A series of parallel cortico-striatal-thalamo- tients, however, have a decline in symptoms Several recent candidate genes have includ- cortical (CSTC) circuits that link specific re- during the adolescence or early adulthood ed: a heterozygous loss of function mutation gions of the frontal cortex to subcortical (Leckman et al., 1998; Bloch et al., 2006), in L-histidine decarboxylase, which encodes structures has provided a framework for un- leading to suggestions of a developmental the rate limiting enzyme in histamine bio- derstanding the interconnected neurobio- disorder. In addition to tics, children with synthesis (Ercan-Sencicek et al., 2010); logical relationships that exist between TS TS often have a variety of comorbid psycho- functional variations of the SLITRK1 and its multiple comorbid problems (Singer pathologies, including attention deficit gene, with homology to a known axon guid- and Harris, 2006; Leckman et al., 2010; hyperactivity disorder (ADHD), obsessive– ance molecule (Scharf et al., 2008); and Mazzone et al., 2010). In classical models of compulsive disorder (OCD), learning diffi- DLGAP3, a postsynaptic scaffolding protein movement disorders the basal ganglia was culties, sleep abnormalities, anxiety, and highly expressed in striatal glutamatergic believed to influence behavior by changing other behaviors, all of which can have a sig- synapses (Crane et al., 2011). cortical excitability through the interplay of nificant impact on the individual’s progno- Multiple factors contribute to the on- the “direct” [striatum to globus pallidus in- sis (Channon et al., 2003; Sukhodolsky et al., going difficulty in identifying a specific terna (GPi)] and the multisynaptic “indi- 2003; Cavanna et al., 2009). The frequent means of genetic transmission, including rect” [striatum to globus pallidus externa occurrence of ADHD and OCD in affected phenotypic heterogeneity, the variable ex- (GPe) to subthalamic nucleus (STN) to individuals has led to suggestions of over- pression of comorbid conditions, genomic GPi] pathway (Albin et al., 1989). Accord- lapping pathophysiology between tic disor- imprinting [sex of the transmitting parent ing to this model, hyperkinetic disorders ders and these conditions. affecting clinical phenotype (Lichter et al., were the result of increased cortical excit- A discussion of treatment is beyond the 1995; Eapen et al., 1997)], bilineal versus ability, due to either a reduction of direct scope of this review and has been described unilineal transmission (Hanna et al., 1999; pathway excitatory effect or an increase in previously (Singer et al., 2010). In brief, Lichter et al., 1999), and epigenetic factors. the indirect inhibitory effect. Since this di- there is no specific cure for tics. The indica- Several studies have suggested that a variety rect/indirect pathway approach failed to ad- tions for initiating tic-suppressing therapy of prenatal and perinatal risks may be asso- dress the specificity of tics, other hypotheses include psychosocial problems, functional ciated with the subsequent development of have been developed that view the basal difficulties, disruptions in the academic or TS, including the timing of perinatal care, ganglia as performing a process of action se- work environment, or physical discomfort. severity of mother’s prenatal nausea and lection, i.e., focused facilitation of selected Available therapies include both behavioral vomiting, proband birth weight, the 5 min movements and inhibition of competing (habit reversal, cognitive behavioral, and re- Apgar score, and prenatal maternal smok- motor patterns (Mink, 2003). Within this laxation therapies) and pharmacological ing (Leckman et al., 1990; Burd et al., 1999; system, tics are viewed as a focal excitatory approaches. The beneficial response to Mathews et al., 2006; Young et al., 2008; abnormality in the striatum that causes an medications affecting specific neurotrans- Pringsheim et al., 2009). Further replica- erroneous inhibition of a group of neurons mitter systems is often used to support a tion, however, is necessary before any signif- in the GPi and in turn a disinhibition of cor- pathological involvement, e.g., improve- icance can be attributed to these factors. The tical neurons (Mink, 2001; Albin and Mink, ment of tics following the use of dopamine emergence of genomic methods that enable 2006). receptor antagonists. comprehensive investigation of both rare and common genetic variations and the Animal models Etiology availability of large patient cohorts is ex- Several animal models have been used to in- Numerous studies have confirmed Gilles de pected to provide valuable insights in the vestigate TS on different bases: (1) face va- la Tourette’s initial suspicion that tic disor- near future (Grados, 2010; State, 2010). lidity, i.e., behaviors or movements that ders are inheritable, but the genetics under- Another proposed theory is that tics have some characteristics resembling motor lying the disorders have proven complicated can be an acquired consequence of auto- tics (e.g., motor stereotypies, sequential (State, 2010). Familial studies have repeat- immune mechanisms following a Group super-stereotypy, repetitive grooming, cir- edly demonstrated significant increases in A ␤-hemolytic streptococcal infection cling, and self injurious behaviors) (Dod- the incidence of TS or other tic disorders in (GABHS) (Swedo et al., 1998; Snider and man et al., 1994; Campbell et al., 2000; first degree relatives of affected individuals Swedo, 2003), a condition labeled as pediat- Berridge et al., 2005; Lo¨scher, 2010; Taylor (McMahon et al., 2003). Studies in twins ric autoimmune neuropsychiatric disorder et al., 2010); or (2) construct validity, i.e., the Felling and Singer • Disease Focus J. Neurosci., August 31, 2011 • 31(35):12387–12395 • 12389 animal model has a pathophysiological or produced repetitive motor tics predomi- gions. This finding is supported by a twin developmental neural circuit deficit that is nantly in the orofacial region (McCairn et study that showed more severely affected consistent with current knowledge concern- al., 2009). Local field potential spikes, siblings to have a smaller right caudate ing TS. Examples in this latter category which correlated with tics, were identified (Hyde et al., 1995) and a longitudinal include the following: a psychostimulant- throughout the cortico-basal ganglia path- study demonstrating that caudate volume induced model; the D1CT-7 transgenic and way. Results suggest that output nuclei of in childhood varied inversely with tic se- dopamine transporter knockdown (DAT- the basal ganglia provide a temporally exact verity in adulthood (Bloch et al., 2005). In KD) mutant mice; a monkey model with and spatially distributed release signal, but contrast, a study using stricter exclusion striatal disinhibition-induced tics; and ro- that the final activation of tics likely occurs criteria to control for confounders failed dent models with immunologically related downstream from basal ganglia output. to demonstrate any changes in caudate basal ganglia dysfunction. volume, but did show increased volume of Autoimmune models the putamen bilaterally in TS boys (Roess- Psychostimulant model Primarily two types of models have been ner et al., 2011). This finding was also The psychostimulant model derives some used to investigate immune mechanisms identified using an automated image anal- relevance based on the ability of dopami- in tic disorders. ysis technique capable of assessing differ- nergic enhancing medications to exacer- Passive transfer of antibodies. This ap- ences throughout the brain rather than bate tics and stimulate locomotor behavior. proach evaluates behavioral effects fol- focusing on specific selected areas (voxel- This rodent model has provided important lowing the infusion of sera or IgG from based morphometry) (Kassubek et al., understandings about the role of the basal individuals with TS into rodent striatum. 2006). Asymmetry of the putamen, with- ganglia, especially striasomes, and the acti- Results remain very controversial. Some out any change in the absolute volumes, vation of stereotypic behaviors (Canales and investigations have shown that sera from has been reported, but results were incon- Graybiel, 2000; Graybiel, 2000). TS subjects produced a significant in- sistent and possibly affected by gender crease in stereotypic behaviors (e.g., licks (Singer et al., 1993; Zimmerman et al., D1 receptor cholera toxin transgenic model and forepaw shakes) as well as episodic 2000). Diffusion tensor imaging (DTI), The D1CT-7 transgenic mouse (produced utterances (Hallett et al., 2000; Taylor et which measures the movement of water, using a transgene made by fusing the pro- al., 2002; Liu et al., 2008). In marked con- provides several indices that can reflect moter region for the human D1 receptor trast, other studies infusing TS or PANDAS microstructural changes. Using this tech- with the intracellular A1 subunit of chol- sera at the same coordinates showed no sig- nique, one group has demonstrated mi- era toxin) clinically demonstrates com- nificant increase in stereotypic behaviors crostructural changes in the putamen pulsive behaviors (repetitive climbing, and no rat developed any audible abnor- compared to healthy controls (Makki et digging, and leaping), biting behaviors, mality (Loiselle et al., 2004). Negative stud- al., 2008). These findings were not repli- and jerking movements (flurries of “twitches” ies were also confirmed in a blinded, cated in a subsequent study, but a correla- of the head, limbs, and trunk) that begin collaborative three-center effort involving tion was identified between the diffusion as early as postnatal day 16 (Burton et al., several of the previously reporting institu- parameters and tic severity among TS pa- 1991; Nordstrom and Burton, 2002). tions (Singer et al., 2005a). tients (Neuner et al., 2011). Jerky movements, similar to what occurs Immunization with GABHS. This model Neuropathological studies of TS pa- in TS, are reduced following treatment evaluates the appearance of autoantibodies tients are rare, but a few studies have pro- with clonidine and D2 antagonists. Ani- and behavioral effects following immuniza- vided evidence of cellular alterations in mals have a reduced seizure threshold tion of mice with GABHS. Female SJL/J the basal ganglia to support imaging stud- which is atypical for children with TS. The mice, immunized and boosted with a ho- ies. In a small study (three TS patients and construct validity of this model for tics is mogenate of GABHS in Freund’s adjuvant, five controls), Kalanithi et al. (2005) based on hyperactivity within cortical, developed immunoreactive antibodies against found increases in the total number of limbic, and corticostriatal circuitry, although mouse cerebellum, globus pallidus, and neurons in the GPi with concomitant its correlation to TS has been questioned thalamus (Hoffman et al., 2004). Rearing decreases in the number and density of neu- (Swerdlow and Sutherland, 2005). and ambulatory behavioral abnormalities rons in the GPe and caudate. The distribu- correlated with IgG deposits in deep cere- DAT-KD mutant mouse tion of parvalbumin-positive GABAergic bellar nuclei. This model relates more to The DAT-KD mouse has a markedly re- interneurons was markedly different in TS pa- mechanisms for GABHS-mediated CNS duced expression of DAT in striatal dopa- tients, with a larger percentage residing in the damage than to either TS or PANDAS mine neurons, and extracellular dopamine GPi. This same group confirmed their find- (Swerdlow and Sutherland, 2005). levels are 170% of wild-type controls ings in two additional patients and further (Zhuang et al., 2001). Behaviorally the ani- demonstrated a decrease in striatal cholinergic mals are hyperactive and have perseverative Structural changes in TS neurons (Kataoka et al., 2010). Although the behaviors and a pattern of more stereotyped Basal ganglia results are limited by a small sample size and and syntactic grooming sequences that re- Volumetric MRI studies, used to identify multiple potential confounders, including sist disruption (Berridge et al., 2005). This neuroanatomical (particularly subcorti- possible effects of pharmacologic therapy, it is model lacks tic-like jerking movements and cal) changes in TS, vary extensively. In the proposed that these findings strongly impli- is more consistent with obsessive–compuls- largest cohort to date, Peterson et al. cate the associative and sensorimotor regions ive-like behaviors. (2003) identified a mild but consistent de- of the basal ganglia in the pathogenesis of TS. crease in basal ganglia volume in a cohort Monkey focal striatal disinhibition of Ͼ150 TS patients. Subdivided by age, Cortex and subcortical white matter In two cynomolgus monkeys, focal disin- the reduced volume was most apparent in Significant evidence exists for a primary hibition of the sensorimotor putamen, us- the caudate of children, with adults show- cortical dysfunction in TS. MRI analyses ing the GABAA antagonist bicuculline, ing reductions across all basal ganglia re- have detected volumetric changes in the 12390 • J. Neurosci., August 31, 2011 • 31(35):12387–12395 Felling and Singer • Disease Focus cortex of TS patients including larger dor- frontal rather than striatal regions (Min- Functional changes in TS sal prefrontal and parieto-occipital re- zer et al., 2004; Yoon et al., 2007a). Transcranial magnetic stimulation gions, and a smaller inferior occipital One pathogenic mechanism proposed for region (Peterson et al., 2001). In a limited Thalamus TS is decreased inhibitory control of the but well controlled male-only study that Structural studies of the thalamus have CSTC circuits. Using TMS to compare 20 excluded medicated patients and those yielded contradictory results. In two small adult TS subjects to healthy controls, in- with comorbidities, voxel-based mor- studies of treatment-naive boys with TS, vestigators demonstrated normal motor phometry and magnetization transfer imag- one found larger left hemithalami (Lee et thresholds but decreased intracortical in- ing (methods sensitive to tissue alterations al., 2005), whereas a second showed bilat- hibition and a shortened cortical silent period in TS patients (Ziemann et al., 1997). and macrostructural integrity) have de- eral decreases in volume as well as micro- A similar shortening of the cortical silent tected changes in prefrontal, frontal, senso- structural changes based on alterations in period was observed in children with TS, rimotor, and anterior cingulate regions fractional anisotropy using DTI (Makki et (Mu¨ller-Vahl et al., 2009). Using parcella- but the changes in intracortical inhibition al., 2008). A third study, using an auto- tion methods, variable changes have been were not found in this group (Moll et al., mated computational anatomy technique, reported in subcortical white matter, with 1999). Across a broad age range, the de- showed no difference in thalamic size be- increases in the right frontal region (Freder- gree of reduction of intracortical inhibi- tween a small group of TS patients and icksen et al., 2002) or decreases in left deep tion appears to correlate with tic severity frontal white matter (Kates et al., 2002). healthy controls, although this study did (Gilbert et al., 2004). Cortical thinning has been observed in fron- not control for numerous variables (Wang Functional neuroimaging tal and parietal lobes, particularly in the sen- et al., 2007). In the largest MRI analysis, in- Event-related PET scanning has corre- sorimotor cortex; the degree of thinning cluding 149 children and adults, there was a lated tic occurrence with activity in a correlated with tic severity (Sowell et al., 5% increase in thalamic volume, primarily number of brain regions, including the 2008). In another study of adults with TS, the lateral thalamus (Miller et al., 2010). Post prefrontal cortex, premotor and primary strength of premonitory sensations corre- hoc testing suggested that the differences ob- motor cortex, anterior cingulate cortex, lated with increased sensorimotor cortical served were not due to IQ, treatment his- putamen, and caudate (Stern et al., 2000). volume (Draganski et al., 2010). Other re- tory, or comorbid conditions. During active tic suppression, there is in- ports evaluating subgroups of TS patients creased activity in the right frontal cortex (e.g., those with simple tics, complex tics, Other brain regions and caudate with decreased activity in the and obsessive–compulsive symptoms) found Several additional brain regions have been globus pallidus, putamen, and thalamus a correlation between the location of cortical implicated in TS. Based on the role of do- using fMRI (Peterson et al., 1998). Several thinning and clinical symptoms (Worbe et al., pamine and known lesions associated PET studies have also identified changes 2010). with other disorders that involve tics, it in regional blood flow consistent with in- Interhemispheric connectivity abnor- was postulated that the midbrain and creased activity in the sensorimotor corti- malities have been suggested by volumetric periaqueductal gray matter might be in- ces and decreased activity in the striatum changes in the corpus callosum (Baumgard- volved in TS (Devinsky, 1983). This hy- and thalamus (Braun et al., 1993; Eidel- ner et al., 1996; Mostofsky et al., 1999; pothesis is supported by voxel-based berg et al., 1997). A small study using Plessen et al., 2004; Cavanna et al., 2010; morphometry demonstrating increased mid- fMRI demonstrated increased activation Roessner et al., 2011), abnormal func- brain gray matter in 31 adult TS patients of the motor cortex during voluntary mo- tional [transcranial magnetic stimulation compared to controls (Garraux et al., tor tasks in TS patients, suggesting altered (TMS)] and structural (DTI) connections 2006). Expanded perivascular spaces in motor organization (Biswal et al., 1998). between the left and right motor hand ar- the midbrain, usually considered a benign One study has also shown that tic severity eas (Margolis et al., 2006; Plessen et al., incidental finding on MRI, have also been correlated positively with activation of the 2007; Baümer et al., 2010), and altered correlated with stereotyped behaviors substantia nigra and ventral tegmentum, performance on a modified verbal di- (Da´vila et al., 2010). Disruption of corti- lending credence to a dopaminergic role. chotic listening task (Margolis et al., 2006; cocerebellar regulatory loops has been This same study found that higher tic se- Plessen et al., 2007; Baümer et al., 2010) postulated based on MRI findings of re- verity correlated with slower cognitive and the bimanual Purdue Pegboard (Mar- duced volumes of the cerebellum, primar- task performance, independent of comor- golis et al., 2006; Plessen et al., 2007; ily gray matter in crus I and lobules VI, bid OCD or ADHD symptoms (Baym et Baümer et al., 2010). Diffusion-weighted al., 2008). In two of the largest fMRI stud- imaging has revealed microstructural al- VIIB, and VIIIA (Tobe et al., 2010). Last, ies, age-related abnormalities in frontos- terations in the corpus callosum and other altered MRI volumes of the hippocampus triatal networks and in frontoparietal white matter (Jackson et al., 2011). Addi- and amygdala (Peterson et al., 2007) and connectivity were identified, suggesting tional support for frontoparietal network DTI diffusion indices (Neuner et al., that TS patients do not undergo normal abnormalities are based on alterations of 2011) has led to suggestions of direct lim- maturational changes (Marsh et al., 2007; MRI resting-state functional connectivity bic involvement in TS. This hypothesis is Church et al., 2009a,b). These findings (Church et al., 2009b), tic generation in supported by hippocampal and amygdala lend support to hypotheses suggesting association with coactivation of the sup- volumes that are larger in pediatric patients that TS is a developmental disorder. plementary motor area (Hampson et al., and significantly smaller in adult patients 2009), appearance of secondary tics after with persistent tics (Peterson et al., 2007). Neurotransmitter studies resection of the frontal lobe (Yochelson The latter suggests a possible failure of nor- Numerous neurotransmitters (dopamine, and David, 2000), and investigations on mal hippocampal plasticity in the minority glutamate, GABA, serotonin, acetylcholine, postmortem tissue showing a greater of patients whose symptoms persist into norepinephrine, and opiates) are involved number of biochemical changes in pre- adulthood. in the transmission of messages through Felling and Singer • Disease Focus J. Neurosci., August 31, 2011 • 31(35):12387–12395 • 12391

Table 1. Summary of TS studies with notes of methods and limitations Reference Technique N (TS) Primary results Comments Structural studies Peterson et al., 2003 Volumetric MRI 154 Reduced caudate volume in TS Post hoc analyses by age, meds, comorbidity Hyde et al., 1995 Volumetric MRI 10 Reduced right caudate volume correlated with symptom Twin study; no control for age, treatment, or common comorbidities severity Bloch et al., 2005 Volumetric MRI 43 Caudate volume in childhood varies inversely with tic Longitudinal design; includes assessment of OCD but not ADHD severity in adulthood effects; no follow-up imaging Roessner et al., 2011 Volumetric MRI 49 Enlarged putamen and corpus callosum in TS Children/adolescents only, controlled for age and IQ; exclusion criteria included prior treatment and comorbid ADHD/OCD Kassubek et al., 2006 Voxel-based morphometry 14 Enlarged putamen in TS Children only; controlled for age and gender, not treatment; assessed ADHD but not OCD effects Singer et al., 1993 Volumetric MRI 37 Altered hemispheric asymmetry of putamen and globus Children only; controlled for age; post hoc analysis of ADHD pallidus comorbidity Zimmerman et al., Volumetric MRI 19 No putamen asymmetry in girls with TS Controlled for age; assessed for ADHD effect 2000 Makki et al., 2008 Diffusion tensor imaging 23 Microstructural abnormalities in thalamus in TS Controlled for age; no analysis of medication or comorbidity effects Neuner et al., 2011 Diffusion tensor imaging 28 Correlation of BG diffusivity and symptom severity Adults only; excluded comorbidities Peterson et al., 2007 Volumetric MRI 154 Larger hippocampus and amygdala in TS Post hoc analyses by age, meds, comorbidity Peterson et al., 2001 Volumetric MRI 155 Enlarged dorsofrontal and parieto-occipital cortices; Post hoc analyses by age, meds, comorbidity diminished inferior occipital cortex Müller-Vahl et al., 2009 Voxel-based morphometry 19 Decreased prefrontal, sensorimotor, anterior cingulate, Adult males only; untreated at least 1 year; no significant and left caudate gray matter; decreased white matter comorbidities in population in right inferior frontal gyrus, left superior frontal gyrus, and anterior corpus callosum Müller-Vahl et al., 2009 Magnetization transfer 19 White matter reductions in right medial frontal gyrus, Adult males only; untreated at least 1 year; no significant imaging inferior frontal gyrus bilaterally, and right cingulate comorbidities in population gyrus Baumgardner et al., Volumetric MRI 37 Larger corpus callosum in TS Children; controlled for age, gender, overall brain volume 1996 Mostofsky et al., 1999 Volumetric MRI 19 No difference in corpus callosum Girls only; assessed effect of ADHD comorbidity Plessen et al., 2004 Volumetric MRI 158 Alterations of corpus callosum, variable with age Post hoc analyses by age, meds, comorbidity Cavanna et al., 2010 DTI 1 Lower fractional anisotropy of corpus callosum Twin comparison Draganski et al., 2010 Voxel-based morphometry 40 Cortical thinning diffusely, modulated based on comor- Post hoc analysis of comorbidities; infers ongoing structural and DWI bidity and symptom severity; increases in primary plasticity based on a single study somatosensory cortex correlated with premonitory sensations Jackson et al., 2011 DWI 13 Diffuse abnormalities in white matter microstructure; Adults; excluded comorbidities; wide range of tic severity enhanced motor control in TS patients Functional studies Ziemann et al., 1997 Transcranial magnetic 20 Shortened cortical silent period and reduced intracortical Adolescent/adult; post hoc analysis by age, sex, comorbidity, and stimulation inhibition treatment Moll et al., 1999 Transcranial magnetic 21 Shortened cortical silent period Children; post hoc analyses of age, OCD, neuroleptic treatment stimulation Gilbert et al., 2004 Transcranial magnetic 36 Correlation of cortical disinhibition with tic and ADHD Children and adults; assessed effects of ADHD and OCD stimulation severity comorbidities Stern et al., 2000 PET 6 Tic correlation with activity in cortex, putamen, and Adults; no control for medication; no discussion of comorbidity caudate Peterson et al., 1998 fMRI 22 Increased cortical activity with decreased striatal and Adults; post hoc analyses of gender, treatment, and comorbidity thalamic activity during active tic suppression Braun et al., 1993 PET 16 Increased activity of sensorimotor cortex; reduction of Adults; nonmedicated activity in limbic cortex and striatum Eidelberg et al., 1997 PET 10 Increased activity in sensorimotor cortex; decreased in Adults; nonmedicated; no assessment of comorbidity effects caudate and thalamus Biswal et al., 1998 fMRI 5 Increased motor cortex activity during voluntary motor Adults, few from same pedigree; variable severity and comorbidities tasks in TS Church et al., 2009b fMRI 33 Abnormal maturation of functional networks Adolescents; included comorbidities Marsh et al., 2007 fMRI 66 Abnormal age-related activation of neural circuits Adults and children; post hoc analysis of medication and comorbidity effects Baym et al., 2008 fMRI 18 Tic severity correlated with enhanced activation of dopa- Children; mostly medication-naive; post hoc analysis of comorbidity; minergic nuclei and slower response time Table continued 12392 • J. Neurosci., August 31, 2011 • 31(35):12387–12395 Felling and Singer • Disease Focus

Table 1. Continued Reference Technique N (TS) Primary results Comments Neurotransmitter studies Wong et al., 2008 PET 16 Increased phasic dopamine release in ventral striatum Adults; included assessment of OCD comorbidity Steeves et al., 2010 PET 8 More widespread phasic dopamine release compared to Adults; controlled for medication exposure and comorbidity controls Liu et al., 2010 SPECT 18 Higher dopamine transporter expression Adolescents and adults; drug-naive; no discussion of comorbidities Behen et al., 2007 PET 29 Abnormal tryptophan metabolism in dorsolateral Children; subgroup analyses of medication and comorbidities prefrontal cortex and thalamus Haugbøl et al., 2007 PET 20 Increased serotonin receptor binding in TS Adult; no assessment of medication or comorbidity effects

CSTC circuits, and each has been proposed familial genetic studies (Barr et al., 1999; ciated with different comorbidities result as a potential pathophysiologic mechanism Tourette Syndrome Association Interna- from distinctly different underlying pa- (Singer and Minzer, 2003). Dopamine dys- tional Consortium for Genetics, 2007; Adam- thologies, yet few studies analyze or con- function is considered a prime abnormality czyk et al., 2010) and reduced levels of trol for this. Many studies peripherally in TS based on tic suppression with the use glutamate in globus pallidus interna, glo- address the comorbid conditions of ADHD of dopamine antagonists (antipsychotics), bus pallidus externa, and substantia nigra and OCD, but again there have been few stud- results from various nuclear imaging proto- pars reticulata in a small number of post- ies to adequately and systematically explore cols (Wolf et al., 1996; Wong et al., 1997, mortem brains (Anderson et al., 1992). the differences between these disorders. 2008; Singer et al., 2002; Albin et al., 2003; Altered cholinergic neurotransmission Questions also remain regarding the mean- Serra-Mestres et al., 2004; Liu et al., 2010), has been implicated by the postmortem ing of the neuroanatomical changes ob- CSF analysis (Singer et al., 1982), and post- finding of decreased numbers of cholin- served in TS patients. Although they may be mortem studies (Singer et al., 1991, 1995; ergic interneurons in the striatum of TS representative of the underlying pathophys- Minzer et al., 2004; Yoon et al., 2007a). One patients (Kataoka et al., 2010). Although iology, they may also be indicative of com- hypothesis is that either an overactive dopa- there is little direct evidence, it has been pensatory changes that have occurred as a mine transporter or central abnormality hypothesized that an alteration of GABAergic result of tics. It would be interesting to study leads to an alteration in phasic dopamine projections from the striatum or an impair- unaffected but at-risk individuals, such as release, which in turn, results in a hyper- ment of cortical inhibition could cause siblings of TS patients, to see whether there responsive spike-dependent dopaminergic TS. Last, since multiple neurotransmitters are neuroanatomic alterations that exist be- system (Singer et al., 2004; Wong et al., interact with adenosine 3Ј,5Ј-monophos- fore the development of tics. As has been 2008). This dopaminergic tonic-phasic phate (cAMP), a postreceptor defect could suggested in a few studies, developmental or hypothesis could potentially involve ei- explain an involvement with multiple trans- maturational changes are likely important ther the cortex or striatum. Although most mitter systems. In a small number of post- in the pathophysiology, but longitudinal neurotransmitter-related studies have fo- mortem brain samples, the amount of studies exploring changes over time are cused on the striatum, support for an extras- cAMP was reduced in several brain regions sparse. triatal dopaminergic dysfunction includes (Singer et al., 1991), but a further study Tourette syndrome provides clinicians, PET findings of decreased cortical receptor showed no abnormality of phosphatidyl- clinician-scientists, and basic researchers with binding potentials and increased dopamine inositol second messenger generating sys- abundant possibilities for future research. release (Steeves et al., 2010) and postmor- tems (Singer et al., 1995). In summary, On the clinical level, it is essential to fur- tem identified cortical dopaminergic abnor- further investigations are required to iden- ther characterize variations in phenotype, malities (Minzer et al., 2004; Yoon et al., tify the underlying biochemical defect in understand the relationship between tics 2007a). this complex disorder. and associated comorbidities, clarify fac- Recognizing the various clinical mani- tors that modify tic behavior, and con- festations seen in TS, it is highly likely that Limitations and Future tinue the search for new and improved this disorder involves a dysfunction of Directions behavioral and pharmacologic therapies. more than one neurotransmitter system After decades of extensive research, the Advanced techniques for evaluating the or a second messenger defect (Singer and pathophysiology underlying TS remains human genome need to be applied to large Minzer, 2003). An altered modulatory effect poorly understood. Interpretation of cohorts with well defined clinical charac- of serotonin in TS has been suggested by the studies is often limited by small sample teristics. The role of the epigenetic modu- combination of diminished levels of the se- sizes, incomplete characterization of the lation requires further attention, both in rotonin transporter and elevated serotonin subjects, varying ages and clinical severity, terms of its ability to potentially modify 2A receptor binding (Wong et al., 2008), as concurrent use of pharmacotherapy, and genetic actions as well as to influence clin- well as PET studies identifying abnormali- diverse statistical methodologies. Table 1 ical behavior. Clarifying the precise neu- ties of tryptophan metabolism in cortical summarizes the studies discussed in this roanatomical location and underlying and subcortical regions (Behen et al., 2007; review, commenting on their methodolo- biochemical mechanism would be a major Haugbøl et al., 2007; Wong et al., 2008). gies and limitations. Even in the studies scientific advance not only for TS, but for Glutamate has an essential role in pathways containing relatively large numbers of pa- multiple other neuropsychiatric disorders involved with CSTC circuits and an exten- tients, there is often little discussion of such as OCD and ADHD. Knowledge of a sive interaction with dopaminergic systems how variation in TS symptomatology and specific biological alteration will enable (Harris and Singer, 2006). Several lines of related comorbidities relates to the find- the direct pursuit of new ways to treat af- evidence support a possible role of the glu- ings. It is certainly possible that simple fected individuals and, dare one say, a tamatergic system in TS including results of tics, complex tics, and tic disorders asso- possible cure. A highly recommended Felling and Singer • Disease Focus J. Neurosci., August 31, 2011 • 31(35):12387–12395 • 12393 source for additional information on TS is dar K, Gernert J, Carson RE, Herscovitch P, Dhawan V, Budman C, Feigin A (1997) The the Tourette Syndrome Association, 42-40 Chase TN (1993) The functional neuroanat- metabolic anatomy of Tourette’s syndrome. Bell Boulevard, Bayside, NY 11361-2820; omy of Tourette’s syndrome: an FDG-PET Neurology 48:927–934. study. I. Regional changes in cerebral glucose Ercan-Sencicek AG, Stillman AA, Ghosh AK, Bil- telephone 718-224-2999; www.tsa-usa.org. metabolism differentiating patients and con- guvar K, O’Roak BJ, Mason CE, Abbott T, trols. Neuropsychopharmacology 9:277–291. 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