Tourette's Syndrome

It's part of my nature.—Jim Eisenreich (1996) Tic disorders have been the subject of intense speculation for at least the last three hundred years. Despite the overt nature of tics and thirty years of scientific scrutiny, our ignorance remains profound. Notions of cause have ranged from “hereditary degeneration” to the “irritation of the motor neural systems by toxic substances, of a self-poisoning bacteriological origin” to “a constitutional inferiority of the subcortical structures …[that] renders the individual defenseless against overwhelming emotional and dynamic forces” (10Kushner H.I A Cursing Brain? The Histories of Tourette Syndrome. Harvard University Press, Cambridge, MA1999Google Scholar). Predictably, each of these etiological explanations has prompted new treatments and ways of relating to families. While tics are common in childhood, full-blown Gilles de la Tourette's syndrome (TS) is not. Boys are more commonly affected than girls. The cardinal features of TS are motor and phonic tics that wax and wane in severity (20Robertson M.M Banerjee S Kurlan R Cohen D.J Leckman J.F McMahon W Pauls D.L Sandor P van de Wetering B.J The Tourette syndrome diagnostic confidence index development and clinical associations.Neurology. 1999; 53: 2108-2112Crossref PubMed Google Scholar). Tics are sudden habitual movements or utterances that typically mimic some fragment of normal behavior and that involve discrete muscle groups. As such, they can easily be confused with normal coordinated movements or vocalizations. Tics can also be mistaken for akathisia, tardive dyskinesia, or other hyperkinetic movement disorders (8Kompoliti K Goetz C.G Hyperkinetic movement disorders misdiagnosed as tics in Gilles de la Tourette syndrome.Mov. Disord. 1998; 13: 477-480Crossref PubMed Scopus (48) Google Scholar). Once established, any given tic tends to persist for a time. Tics are often exacerbated by stress and fatigue. In contrast to other movement disorders, tics can occur during sleep but are usually much attenuated. Motor and phonic tics occur in bouts over the course of a day and wax and wane in severity over the course of weeks to months. Less well known is the “self-similarity” of these temporal patterns across different time scales (17Peterson B.S Leckman J.F The temporal dynamics of tics in Gilles de la Tourette syndrome.Biol. Psychiatry. 1998; 44: 1337-1348Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). It has recently been documented that the frequency distribution of intertic interval durations follows an inverse power law of temporal scaling. In addition, first return maps demonstrated “burst-like” behavior and short-term periodicity, proving that successive tic intervals are not random events. These findings provide suggestive, though not conclusive, evidence for the presence of fractal, and possibly chaotic, processes. Application of nonlinear dynamical methods may provide insight into the temporal features of tics that commonly are described clinically, such as short-term bouts or bursting and longer term waxing and waning. A deeper understanding of the multiplicative processes that govern these timing patterns may clarify both microscopic neural events occurring in millisecond time scales as well as macroscopic features of the natural history of tic disorders. Motor tics typically begin between the ages of 3 and 8 with transient periods of intense eye blinking or some other facial tic. Vocal tics such as repetitive bouts of sniffing or throat clearing may begin as early as 3 years of age, but typically, they follow the onset of motor tics by several years. In uncomplicated cases, motor and vocal tic severity peaks early in the second decade with many patients showing a marked reduction in tic severity by the age of 19 or 20 (13Leckman J.F Zhang H Vitale A Lahnin F Lynch K Bondi C Kim Y.-S Peterson B.S Course of tic severity in Tourette syndrome the first two decades.Pediatrics. 1998; 102: 14-19Crossref PubMed Scopus (470) Google Scholar). However, the most severe cases are adults. Extreme forms of this illness involve forceful bouts of self-abusive motor tics such as hitting or biting and socially stigmatizing coprolalic utterances. Many patients with tic disorders report the presence of associated sensory phenomena including “faint” premonitory urges that incessantly prompt the tics and feelings of momentary relief that follow the performance of a tic (3Bliss J Sensory experiences of Gilles de la Tourette syndrome.Arch. Gen. Psychiatry. 1980; 37: 1343-1347Crossref PubMed Scopus (172) Google Scholar). Many patients describe these sensations as being bodily feelings that are localized to discrete anatomical regions—like an urge to itch or a need to clear one's throat. Other antecedent sensory phenomena include a generalized inner tension that can be relieved only by the performance of a particular tic. Specific auditory or visual cues can also prompt tics in some patients. The range of these cues is enormous but highly selective for individual patients—a cough, a particular word, an alignment of angles, or specific shapes. In addition to tics, many TS patients suffer from symptoms of obsessive-compulsive disorder and/or attention deficit hyperactivity disorder. When present, these coexisting conditions can add greatly to the morbidity associated TS (11Leckman J.F Cohen D.J Tourette's Syndrome. John Wiley and Sons, New York1998Google Scholar). Habits are assembled routines that link sensory cues with motor action. They allow us to act without thinking—like riding a bicycle, driving a car, or delivering a well-rehearsed speech. As such, they are enormously adaptive and part of a common evolutionary heritage that we share with other vertebrates as we engage in goal-directed behavior. When we do things over and over again, we get better at it. There is less thinking about the action, and we can respond in a more nuanced manner to other environmental cues. How does brain manage these marvels? It appears likely that these events involve neural loops or spirals that connect the basal ganglia with the cortex and thalamus (Figure 1; 6Graybiel A.M The basal ganglia and chunking of action repertoires.Neurobiol. Learn. Mem. 1998; 70: 119-136Crossref PubMed Scopus (664) Google Scholar). The motor, sensorimotor, association, and inhibitory neural circuits that course through the basal ganglia are commonly referred to by their successive processing components and are therefore called “cortical-striatal-thalamo-cortical” (CSTC) circuits. CSTC circuits are composed of multiple, partially overlapping, but largely “parallel” circuits that direct information from the cerebral cortex to the subcortex and then back again to specific regions of the cortex, thereby forming multiple cortical-subcortical loops. Although multiple anatomically and functionally related cortical regions provide input into a particular circuit, each circuit in turn refocuses its projections back onto only a discrete subset of the cortical regions initially contributing to that circuit's input. Within the basal ganglia and thalamus, each of the circuits appears to be microscopically segregated from others that course through the same macroscopic structure—hence the conceptualization of these overlapping pathways as being “parallel.” Although the number of anatomically and functionally discrete pathways is still the subject of controversy, the current consensus holds that CSTC circuitry has at least three components—those initiating from and projecting back to sensorimotor, orbitofrontal, or association cortices. Other functional components of CSTC circuitry likely exist and probably include those traditionally associated with the limbic system. Based largely on work performed in Graybiel's laboratory, it appears that the response of particular medium spiny projection (MSP) neurons in the striatum is frequently dependent upon a selective set of perceptual cues and environmental conditions, suggesting that the coordinated striatal response is acquired through learning and experience. Inputs from ascending dopamine pathways originating in the substania nigra, pars compacta, play a crucial role in this learning process (Figure 1; 1Aosaki T Graybiel A.M Kimura M Effect of the nigrostriatal dopamine system on acquired neural responses in the striatum of behaving monkeys.Science. 1994; 265: 412-415Crossref PubMed Scopus (300) Google Scholar). Ensemble recordings, in which the activity of multiple MSP neurons are recorded simultaneously, have begun to clarify the role of the striatum and related brain circuits in the learning and production of habitual or “automatic” behavioral responses. Recently, Graybiel and colleagues have recorded from ensembles of electrodes in the sensorimotor areas of rat striatum during cued learning tasks. Their results demonstrated large-scale changes in recruitment and firing patterns of these neurons (7Jog M.S Kubota Y Connolly C.I Hillegaart V Graybiel A.M Building neural representations of habits.Science. 1999; 286: 1745-1749Crossref PubMed Scopus (614) Google Scholar). Of special interest was the tendency of the number of units firing at the start and end of goal-directed activity to increase asymptotically during successive stages of learning. Animal studies have also indicated that the balance of activity of MSP neurons located in the striosomes versus the matrix of the striatum may crucially determine an individual's vulnerability to dopamine-mediated stereotypies (Figure 1; 4Canales J.J Graybiel A.M A measure of striatal function predicts motor stereotypy.Nat. Neurosci. 2000; 3: 377-383Crossref PubMed Scopus (306) Google Scholar). These stereotypies include a range of repetitive tic-like head and paw movements, as well as repetitive sniffing. If habits are coordinated ensembles of thought and action, then conceptually tics or stereotypies may be best seen as those prewired bits of behavior that are available to be assembled into habits. Like habits, tic action sequences often arise from a heightened and selective sensitivity to environmental cues from within the body or from the outside world. These perceptual cues include faint premonitory feelings or urges that are relieved with the performance of tics and a need to perform tics or compulsions until they are felt to be “just right.” Although the neural mechanisms that conspire to produce tics have yet to be elucidated, preliminary evidence suggests that they involve the same structures that underlie habit formation. The basal ganglia and their open-ended neural loops and their cortico-cortical connections have long been a focus of TS research. Advances in neuroimaging and neurophysiological techniques have made it possible to examine these circuits in living subjects. In TS there is preliminary evidence that voluntary tic suppression involves activation of regions of the prefrontal cortex and caudate nucleus and bilateral deactivation of the putamen and globus pallidus (18Peterson B.S Skudlarski P Anderson A.W Zhang H Gatenby J.C Lacadie C.M Leckman J.F Gore J.C A functional magnetic resonance imaging study of tic suppression in Tourette syndrome.Arch. Gen. Psychiatry. 1998; 55: 326-333Crossref PubMed Scopus (374) Google Scholar). If confirmed, these findings are consistent with the well-known finding that chemical or electrical stimulation of inputs into the putamen can provoke motor and vocal responses that resemble tics. They also suggest that prefrontal cortex-basal ganglia circuits participate in shaping of the inhibitory influence of the output neurons in the internal segment of the globus pallidus and the pars reticulata of the substania nigra. Most functional magnetic resonance imaging (fMRI) studies to date have employed a block design in which the activation/deactivation signal reflects a presumed continuous mental state. More recently, event-related fMRI techniques have been developed that will greatly enhance the temporal resolution of these studies. Work in progress suggests that it should be possible to monitor individual tics as they occur in the magnet. These studies should permit investigators to begin to define the temporal sequence of activity within different portions of these cortical-subcortical loops. In this regard, it will be intriguing to study the involvement of the supplementary motor area as electrical stimulation of the SMA elicits a variety of bodily sensations that include premonitory sensations or “urges” to perform a movement or a sense of anticipation that a movement is about to occur (5Fried I Katz A McCarthy G Sass K.J Williamson P Spencer S.S Spencer D.D Functional organization of human supplementary motor cortex studied by electrical stimulation.J. Neurosci. 1991; 11: 3656-3666Crossref PubMed Google Scholar). As with habits and stereotypies, ascending dopaminergic pathways likely play a key role in the consolidation and performance of tics. First, dopamine D2 receptor blocking agents are the mainstay of traditional pharmacological approaches to the treatment of tics (19Riddle, M.A., and Carlson, J. (2000). In Tourette Syndrome, D.J. Cohen, C.G. Goetz, and J. Jankovic, eds. (Philadephia, PA: Lippincott, Williams & Williams), in press.Google Scholar). Second, studies of monozygotic twins indicate that developmental shifts in the balance of tonic-phasic dopaminergic tone occur as a result of epigenetic differences, and the density of dopamine D2 receptors may influence the severity of TS (29Wolf S.S Jones D.W Knable M.B Gorey J.G Lee K.S Hyde T.M Coppola R Weinberger D.R Tourette syndrome prediction of phenotypic variation in monozygotic twins by caudate nucleus D2 receptor binding.Science. 1996; 273: 1225-1227Crossref PubMed Scopus (211) Google Scholar). Although future ligand-based functional imaging studies in child and adolescent samples complemented by neuropathological studies hold considerable promise to elucidate these mechanisms, ethical concerns and logistic difficulties may limit these avenues of investigation, which in turn points to the need to develop suitable animal models for TS and related disorders (23Swerdlow N.R Young A.B CNS Spectrums. 1999; 4: 65-74Crossref Scopus (10) Google Scholar). TS is a familial disorder (15Pauls D.L Raymond C.L Stevenson J.M Leckman J.F A family study of Gilles de la Tourette syndrome.Am. J. Hum. Genet. 1991; 48: 154-163PubMed Google J study and of Tourette syndrome evidence for a of J. Hum. Genet. 1996; Google Scholar). of is progress in the of TS Tourette for in affected by Gilles de la Tourette syndrome.Am. J. Hum. Genet. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). Building on the results of a of affected this of investigators is maps of several regions in an to and their preliminary results in a new of as well as in families. is for with an of and has been in studies of other disorders, such as in two on and on are of While it is that of the regions 3 8 and in which have been to with TS any evidence for it is still possible that TS may be in or more of these regions of the regions in which been with such as and by the results of this progress is about the nature and normal of a of the TS is likely to provide a in understanding TS the decade has seen the of an area of that is the that mechanisms to the of some TS a at least a for tic disorder symptoms from the It is well that A can in is a of occurring weeks an is by the and/or system and TS share common basal ganglia of the brain and the related cortical and some patients motor and vocal tics as well as obsessive-compulsive and suggesting the that at least in some these disorders share a common As in have been to be in the of some patients with TS J.J M against human putamen in with Tourette 1998; PubMed Scopus Google Scholar). It has been that with a clinical and and some cases of TS and evidence from M S S J disorders associated with clinical of the first J. Psychiatry. 1998; Google that in was likely to have onset for of the onset for of the Although the etiological of the and the association with remains a of considerable R Tourette's syndrome and will the 1998; PubMed Scopus Google on this promise S and for obsessive-compulsive disorder and tic disorders in 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). specific are associated with onset or clinical then the nature of these should provide insight as to the and mechanisms may provide a for the design of and for TS is usually the of this has not been and for any Many cases of TS can be without When patients with coexisting and/or it is often better to these conditions as treatment of these disorders will often tic treatments are not of the agents or techniques can be tics are at their Most of the available pharmacological agents and many have for some it is much to treatment than to or it. in the term is in more than of cases, but than on the of on and The and of treatments are in for Tourette's and for the as a to the of other symptoms or responses are for to for a well pharmacological D2 term to and for tardive and and Leckman for early for two for marked in the age or for in clinical for in a number of for and not available in the receptor and and Leckman for in a number of well on in a number of on treatment with and is not for or with a number of patients well in the on of with for and and Leckman for or in a number of on for the in a number of on for in a of with the for and and Leckman for for in a number of for some versus frequency stimulation of in a number of with the for best to be magnetic in a number of best stimulation for to be least clinical has been or M.A., and Carlson, J. (2000). In Tourette Syndrome, D.J. Cohen, C.G. Goetz, and J. Jankovic, eds. (Philadephia, PA: Lippincott, Williams & Williams), in press.Google and Cohen, Goetz, and Jankovic, J. (2000). Tourette of the In Tourette Syndrome, D.J. Cohen, C.G. Goetz, and J. Jankovic, eds. (Philadephia, PA: Lippincott, Williams & Williams), in press.Google for in a new least clinical has been progress in the and treatment on Tourette's be greatly with the development of animal present, and stereotypies to the promise (Figure 1; J.F Cohen D.J Anderson Pauls D.L The of Gilles de la Tourette's syndrome a of and A.B Press, New Google Scholar). If tics, stereotypies, to the balance of activity MSP neurons in the and matrix of the striatum (Figure 1; 4Canales J.J Graybiel A.M A measure of striatal function predicts motor stereotypy.Nat. Neurosci. 2000; 3: 377-383Crossref PubMed Scopus (306) Google then it should be possible to examine the clinical of and/or developmental that the number and sensitivity of MSP neurons in the two striatal and increase the of tic disorders R J.F C in at age years to Gen. Psychiatry. PubMed Scopus Google Scholar). they also increase an to develop stereotypies in response to If is there evidence of a to MSP neurons in the this may provide a of about tics from a number of including the stress of tics the presence of premonitory sensory urges sensory motor and motor cortical inputs on the in the the reduction of tics an individual is in that selective attention and motor action activity within the matrix and the need to sensory and motor in a of information from both and motor neurons on MSP within the The timing of tics and the course of tic disorders may be in the firing of dopaminergic a developmental it is clear that many of the of the cerebral cortex from the same regions in the that also to the MSP neurons of the striatum of and in early 1999; PubMed Scopus Google Scholar). events occurring at a specific in development for both the striatal and the seen in some patients with Tourette's syndrome W A motor in Tourette's disorder evidence from magnetic J. Psychiatry. it is to that in and in forms of Tourette's the functional activity of the MSP neurons of the matrix is as a result of the is that the in a subset of TS patients may and the balance between the and of the of TS have been by in systems and the understanding of the role of the basal ganglia in learning and habit formation. Although the evidence that the same mechanisms are in both habit and tics is progress in systems and functional in neuroimaging has set the for a in our understanding of in these areas will to the of specific brain circuits for more and can also be which circuits are and to How does that of involvement the course and it be possible to treatment response neuroimaging will specific stimulation to cases V van C J treatment of Gilles de la Tourette syndrome by frequency stimulation of 1999; Full Text Full Text PDF PubMed Scopus Google