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Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. TouretteSyndromeandTicDisorders: ADecadeofProgress JAMESE.SWAIN,M.D.,P H .D.,F.R.C.P.C.,LAWRENCESCAHILL,M.S.N.,P H .D., PAULJ.LOMBROSO,M.D.,ROBERTA.KING,M.D., AND JAMESF.LECKMAN,M.D. ABSTRACT Objective: ThisisareviewofprogressmadeintheunderstandingofTourettesyndrome(TS)duringthepastdecade includingmodelsofpathogenesis,state-of-the-artassessmenttechniques,andtreatment. Method: Computerized literaturesearcheswereconductedunderthekeywordsTourettesyndrome,Tourettedisorder,andtics.Only referencesfrom1996 Y 2006wereincluded. Results: StudieshavedocumentedthenaturalhistoryofTSandthefinding thatticsusuallyimprovebytheendoftheseconddecadeoflife.IthasalsobecomeclearthatTSfrequentlyco-occurswith attention-deficit/hyperactivitydisorder),obsessive-compulsivedisorder,andarangeofothermoodandanxietydisorders. Thesecomorbidconditionsareoftenthemajorsourceofimpairmentfortheaffectedchild.Advanceshavealsobeenmade inunderstandingtheunderlyingneurobiologyofTSusinginvivoneuroimagingandneurophysiologytechniques.Progress onthegeneticfronthasbeenlessrapid.Properdiagnosisandeducation(involvingtheaffectedchildandhisorher parents,teachers,andpeers)areessentialprerequisitestothesuccessfulmanagementofchildrenwithTS.When necessary,modestlyeffectiveantiticmedicationsareavailable,althoughinterveningtotreatthecomorbidattention-deficit/ hyperactivitydisorderand/orobsessive-compulsivedisorderisusuallytheplacetostart. Conclusions: Prospective longitudinalstudiesandrandomizedclinicaltrialshaveledtotherefinementofseveralmodelsofpathogenesisand advancedourevidencebaseregardingtreatmentoptions.However,fullyexplanatorymodelsareneededthatwouldallow formoreaccurateprognosisandthedevelopmentoftargetedandefficacioustreatments. J.Am.Acad.ChildAdolesc. Psychiatry, 2007;46(8):947 Y 968. KeyWords: Tourettedisorder,Tourettesyndrome,ticdisorder,review. Ticshavebeenthesubjectofmedicalspeculationfor hundredsofyears(Kushner,1999).Putativeexplana- tionsfortheoccurrenceofticsandtheirhighdegreeof variabilityhaveincludedinheritedfactors,influenceof toxins,andemotional,psychological,orinfectious processes.Althoughmajorgapsremaininourknowl- edgeoftheetiologyofticsandthemosteffective treatment,thepastdecadehasseensignificantadvances inourunderstandingoftheneurophysiological mechanismsatwork.Althoughnoidealtreatmentfor ticshasbeenestablished,randomizedclinicaltrialshave clarifiedtheshort-termbenefitsofanumberofagents. Thisreviewsummarizestheclinicalfeaturesoftics, beforebrieflyconsideringcurrentmodelsofpathogen- esisandevidence-basedinterventionsforTourette syndrome(TS)andrelatedconditions. PHENOMENOLOGY TSisadevelopmentalneuropsychiatricdisorderwith childhoodonset.ThereisnodiagnostictestforTS. Accordingto DSM-IV-TR (AmericanPsychiatric Association,2000),itischaracterizedbybrief,stereo- typical,butnonrhythmicmovementsandvocalizations AcceptedMarch13,2007. Drs.Swain,Scahill,Lombroso,King,andLeckmanarewiththeChildStudy CenterofYaleUniversity,NewHaven,CT;andDr.Scahillisalsowiththe SchoolofNursingatYaleUniversity. ThisworkwassupportedinpartbyNIHgrantsMH49351,MH061940, MH61940,MH01527,MH52711,MH076273,andRR00125;theNational AssociationofResearchonSchizophreniaandDepression;theTouretteSyndrome Association;theSmartFoundation;JayandJeanKaiser;TheRembrandt Foundation;TheChrysosFoundation;andtheChasanoffFamily,aswellasgifts fromAssociatesoftheYaleChildStudyCenterandanonymousdonors.The authorsalsothankVirginiaEicher,NancyThompson,andMoniqueStaggersfor editorialsupport. CorrespondencetoDr.JamesF.Leckman,YaleChildStudyCenter,230 SouthFrontageRoad,P.O.Box207900,NewHaven,CT06520-7900;e-mail: james.leckman@yale.edu. 0890-8567/07/4608-0947
2007bytheAmericanAcademyofChild andAdolescentPsychiatry. DOI:10.1097/chi.0b013e318068fbcc RESEARCHUPDATEREVIEW 947 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. calledtics.Commonticsincludeeyeblinking,grimac- ing,jaw,neck,shoulderorlimbmovements,sniffing, grunting,chirping,orthroatclearing.Inthenatural historyofTS,motorticsoftenbeginbetweentheages of3and8,severalyearsbeforetheappearanceofvocal tics.Ticstypicallyfollowawaxingandwaningpattern ofseverity,intensity,andfrequency(Leckmanetal., 1998;Linetal.,2002;Robertsonetal.,1999).Tic severityusuallypeaksearlyduringtheseconddecadeof lifewithmanypatientsshowingamarkedreductionin severitybytheendofadolescence(Blochetal.,2006a; Coffeyetal.,2004;Leckmanetal.,1998;Pappertetal., 2003).Only20%orfewerofchildrenwithTS continuetoexperienceamoderatelevelofimpairment ofglobalfunctioningbytheageof20years(Blochetal., 2006a).However,ticdisordersthatpersistinto adulthoodcanbeassociatedwiththemostsevere symptomsincludingviolentepisodesofself-injurious motortics(secondarytohittingorbiting)orsocially stigmatizingcoprolalicutterancesorgestures(e.g., shoutingobscenitiesorracialslurs). Thedescriptionofticsassimplyintermittenttrains ofinvoluntarymotordischargeisincomplete.Many ticsareoftenunderpartialvoluntarycontrol,evidenced bypatients ` capacitytosuppressthemforbriefperiods oftime.Arelatedfeatureofticsisthattheyare frequentlyassociatedwithantecedentsensoryphenom- ena,includingageneralsenseofinnertensionorfocal ‘‘premonitoryurges.’’Theseurgescanbeexperiencedas nearlyirresistible.Theycanbeamajorsourceof impairment.Anineffableandfleetingfeelingofrelief oftenfollowsperformanceofaticorseriesoftics (Banaschewskietal.,2003;Kwaketal.,2003a). Ticsoftenoccurindiscreteboutsovertimescalesof daystoyears(PetersonandLeckman,1998).Thebouts arecharacterizedbybriefperiodsofstableintertic intervalsofshortduration,typically0.5to1.0seconds. Theseboutsofticshavebeenshowntooccurinbouts andinterboutintervalsthatmaylastfromminutesto severalhourstoevenlongerperiods.Itispossiblethat thewaxingandwaningofticseverity(overthecourseof months)andthepeakingofworst-everticseverityearly intheseconddecadeoflifemayreflectthesame multiplicativeprocessesthatgovernthetimingoftic expression.Adeeperunderstandingoftheseeventsmay occuraswebegintounderstandtheneuralevents involvedinticgeneration(atthemillisecondtimescale) (Leckmanetal.,2006). Ticsarealsosensitivetoanumberoffactors includingeverydaypsychosocialstress,anxiety,emo- tionalexcitement,andfatigue(Findleyetal.,2003; Hoekstraetal.,2004a).Interestingly,activitiesthat requirefocusedattentionandfinemotorcontrol,such asreadingaloud,playingamusicalinstrument, engagingincertainsports(andevenperforming surgery)arecommonlyassociatedwiththetransient disappearanceoftics. Althoughmuchdiminished,ticscanoccurduring sleep.Polysomnographicstudiesindicatethatsleep disturbanceisfrequentlypartoftheTSpicturewitha decreasedqualityofsleepandincreasedarousal phenomena(Cohrsetal.,2001;Kostanecka-Endress etal.,2003).Associatedcomorbidities,particularly attention-deficit/hyperactivitydisorder(ADHD)are alsolikelytocontributetosleepingdifficulties (Ivanenkoetal.,2004). COMORBIDITY Simpleandtransientticsintheabsenceofcomorbid conditionsarecommonandoccurinatleast5%of children(KhalifaandvonKnorring,2003).Inclinical samplesTSaloneistheexceptionratherthantherule (Scahilletal.,2005).ADHDisfrequentlydiagnosedin childrenwithTS,withaprevalenceashighas60%to 70%(Coffeyetal.,2000;Eapenetal.,2004;Spencer etal.,1998).AhighfrequencyofcomorbidADHDhas alsobeenobservedincommunitysamples(Khalifaand vonKnorring,2005;Kurlanetal.,2002;Scahill, 2005).Thisco-occurrenceofTSandADHDcanbe associatedwithdisruptivebehaviorssuchasaggression, explosivebehavior,lowfrustrationtolerance,and noncompliance(Budmanetal.,2000;Kurlanetal., 2002;Snideretal.,2002).WhencomorbidADHDis present,itisfrequentlyassociatedwithacademic difficulties,peerrejection,andfamilyconflict(Carter etal.,2000;Hoekstraetal.,2004c;Petersonetal., 2001a;Spenceretal.,2001;Sukhodolskyetal.,2003). Therelationshipofaggressiveandexplosivebehavior (‘‘rageattacks’’)withTSisunclearandcontroversial (Budmanetal.,2000). Inclinicalsamplesabout50%ofpatientswithTS haveprominentobsessive-compulsive(OC)symptoms. OCdisorder(OCD)isfarmorecommoninchildren andadultswithTSthanwithoutTS(Amercian PsychiatricAssociation,2000).Analysisofvertical SWAINETAL. 948 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. transmissionpatternsinfamiliessuggeststhatOCD andTSmaysharesomeofthesameunderlyinggenetic vulnerability(Pauls,2003).Ofnote,‘‘tic-related’’ OCDisemergingasaspecificsubtypeofOCD (Migueletal.,2005).Severalclinicalserieshave documentedthatindividualswithatic-relatedform ofOCDaremorelikelytoreportobsessionsof symmetryandexactnessandaneedtodoandredo activitiestoachieveasenseofcompletionorasenseof thingslooking,feeling,orsounding‘‘justright’’(Kwak 2003a;Woodsetal.,2005).Childrenandadolescents withOCDareimpairedinmultipledomainsof adaptiveandemotionalfunctioning.Whencomorbid OCDispresentalongwithADHD,thereisan additionalburdenonsocial,school,andfamily functioning(Sukhodolskyetal.,2005). Theco-occurrenceofdepressionandanxietysymp- tomswithTSmayreflectthecumulativepsychosocial burdenofhavingticsorsharedbiologicaldiatheses (Coffeyetal.,2000;Kurlanetal.,2002;Linetal., 2006).Thefourfoldincreaseinthefrequencyof migrainesinpatientswithTS(Kwaketal.,2003b) suggestsapossiblesharedetiology(Barbantiand Fabbrini,2004;Breslauetal.,2003).Co-occurrence withautismhasalsobeenreported.Indeed,among autisticsubjects,theprevalenceofTShasbeenreported tobe6.2%,about10timestheprevalenceofthegeneral population(Baron-Cohenetal.,1999;Kadesjoand Gillberg,2000). EPIDEMIOLOGY ChronicmotorandphonicticsandTShavebeen observedtheworldover,suggestingthatitisnotculture bound.PrevalenceratesofTSandrelatedconditions varyaccordingtothesource,age,andsexofthesample; theascertainmentprocedures;anddiagnosticsystem. Onceconsideredanextremelyraredisorder,current estimatesoftheprevalenceofTSareapproximately4to 6/1,000childreninEuropeanandAsianpopulations (Jinetal.,2005;KhalifaandvonKnorring,2003, 2005;WangandKuo,2003).Bycontrast,simpleand transientticsarequitecommon,affectingupto6%to 20%ofallchildren(KhalifaandvonKnorring,2003; Kurlanetal.,2002;Robertson,2003). Epidemiologicalstudiesinvolvingdirectobservation indicateahighestprevalenceofticsinthegeneral populationpeakat3to5yearsofage(thetypicalageat onsetforTS)andat9to12yearsofage(whenthetics ofTSusuallyreachtheirworst-everpoint)(Gadow etal.,2002). DIFFERENTIALDIAGNOSIS Anumberofconditionsproducesymptomsresem- blingtheticsofTS,includingmyoclonus,tremors, chorea,athetosis,dystonias,akathisicmovements, paroxysmaldyskinesias,andballisticmovements (KompolitiandGoetz,1998;KraussandJankovic, 2002;Saunders-Pullmanetal.,1999).Thedifferential diagnosisofTSincludesgeneticconditionssuchas Huntington ` schorea,metabolicdiseasessuchas Wilson ` sdisease,structuraldiseasesasinhemiballismus associatedwithinsulttothesubthalamicnucleus,post- infectiousautoimmuneprocessessuchasSydenham ` s chorea(SC),neuroacanthocytosis,andsideeffectsof antipsychoticmedicationssuchasthedystoniasand akathisia. Complexmotorticsmayappearidenticaltoother purposivemovements(youknowtheyareticsbecause theyreappearrepeatedlyinbouts).Inappearance complexticsmayalsobeindistinguishablefromsome compulsiverituals,buttheycanbedistinguishedbased ontheantecedentpresenceofeitherpremonitoryurges orobsessionalthoughts.ThediagnosisofTSshouldbe indoubtintheabsenceofsimpletics.Vocalticscanbe helpfulinrulingoutotherdiagnosesbecausetheyare rareinotherneurologicalconditions.Exceptions includeHuntington ` sdiseaseandSC(Mercadante etal.,1997). ETIOLOGY Astressdiathesismodelinvolvingtheinteractionof geneticandenvironmentalriskfactorsisfrequently invokedtoexplainthevariableexpressionoftic disorders.TheobservedassociationbetweenTS symptomsandstressfullifeeventshasbeennoted sincetheinitialdescriptionbyGillesdelaTourette. Suchcontributingproblemsmayfindacommonfinal pathwayinthehypothalamic-pituitary-adrenalaxisand theassociatedstress-rela tedneurotransmittersand hormonesandtheirtargets.Insupportofthis,data suggestthatTSpatientsmayhaveaheightened reactivityofthehypothalamic-pituitary-adrenaland noradrenergicsympatheticsystemsascomparedwith 10-YEARREVIEW:TOURETTESYNDROMEANDTICS 949 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. healthycontrolsubjects(Chappelletal.,1996;Findley etal.,2003). Genetics Geneticvulnerabilityfactorshavebeenimplicatedin theverticaltransmissionofTSandrelateddisorders (Pauls,2003).Thepatternofhereditarytransmission, inwhichtwinstudiesrevealedhighconcordancerates inmonozygoticbutnotdizygotictwins,initially suggestedmajorgeneeffects.Indeed,theresultsof segregationanalysesareconsistentwithmodelsof autosomaltransmissionsetagainstapolygenicback- ground.Familygeneticstudieshavealsoreinforcedthe viewthatTSandsomeformsofOCDandADHDare etiologicallyrelatedtooneanother(Leckmanetal., 2003;McMahonetal.,2003;Migueletal.,2005; Nestadtetal.,2002). Linkagestrategieshavesuggestedtheimportance ofseveralchromosomalregions,including11q23 (Meretteetal.,2000),4q,and8p(TouretteSyndrome AssociationInternationalConsortiumforGenetics, 1999).However,arecentefforttoconfirmandextend thefindingsfromtheTouretteSyndromeAssociation InternationalConsortiumforGeneticshasledtothe identificationofnewregionsandafailuretoreplicate theoriginalfindings(DavidPauls,personalcommu- nication,2005). Identity-by-descentapproaches,atechniquethat assumesthatafewfounderindividualscontributed thevulnerabilitygenesthatarenowdistributedwithina muchlargerpopulation,havebeenusedtostudyTS populationsinSouthAfrica,CostaRica,andFrench- speakingCanada(Mathewsetal.,2004).They implicateregionsnearthecentromereofchromosome 2aswellas6p,8q,11q,14q,20q,21q(Simonicetal., 1998),andX(Diaz-Anzalduaetal.,2004).Another largepedigreestudyintheUnitedKingdominvolving linkageanalysisofTSpatientsissuggestiveoflinkage atlocionchromosomes5,10,and13(Curtisetal., 2004). Inaddition,anumberofcytogeneticabnormalities havebeenreportedinTSfamilies(3[3p21.3],7 [7q35 Y 36],8[8q21.4],9[9pter],and18[18q22.3]; Cukeretal.,2004;Stateetal.,2003).Amongthemore recentfindings,Verkerketal.(2003)reportedthedis- ruptionofthecontactin-associatedprotein2geneon chromosome7.Thisgeneencodesamembraneprotein locatedatnodesofRanvierofaxonsthatmaybe importantforthedistributionoftheK + channels,which wouldaffectsignalconductionalongmyelinated neurons.Mostrecently,Abelsonetal.(2005)identified andmappedadenovochromosome13inversionina patientwithTS.Thegene SLITRK1 wasidentifiedasa brain-expressedcandidategenemappingapproximately 350kbfromthe13q31breakpoint.Mutationscreening of174patientswithTSwasundertakenwiththe resultingidentificationofatruncatingframe-shift mutationinasecondfamilyaffectedwithTS.In addition,twoexamplesofararevariantwereidentified inahighlyconservedregionofthe3 ¶ untranslatedregion ofthegenecorrespondingtoabrain-expressedmicro- RNAbindingdomain.Invitrostudiesshowedthatboth theframeshiftandthemicro-RNAbindingsitevariant hadfunctionalpotentialandwereconsistentwithaloss- of-functionmechanism.Studiesofboth SLITRK1 and themicro-RNApredictedtobindinthevariant- containing3 ¶ regionshowedexpressioninbasalganglia anddeeplayersofcortex(inbothmouseandhuman). Futureresearchisneededtoconfirmandexpandonthe initialfindings.Forexample,ifthecandidategene Slit andTrk-likefamilymember1( SLITRK1 )isconfirmed asageneofmajoreffect,validanimalmodelsofTS shouldbeforthcoming. Withrareexceptions,suchas SLITRK1 ,itislikely thatmultiplevulnerabilitygenesplayaroleinthe expressionofTSandrelateddisorders(Leckmanetal., 2003;Zhangetal.,2002).Basedoncurrenttheoriesof thepathogenesisofTS,severalcandidategeneshave beenassessedinpeoplewithTS,includingvarious dopaminereceptors( DRD1 , DRD2 , DRD4 ,and DRD5 ),thedopaminetransporter,variousnoradrener- gicgenes( ADRA2a , ADRA2C , DBH, and MAO-A ), andafewserotonergicgenes( 5HTT ;Cheonetal., 2004;Comings,2001;Leeetal.,2005).Genetic variationatanyoneoftheselociisunlikelytobea majorsourceofvulnerabilitytothedisorder,butin concerttheseallelescouldhavecumulativeeffectsand contributetophenotypicvariability. Ultimately,toexplaincomplexdisorderswith complexcomorbiditiessuchasTS,manytechniques willbeneeded.Moreworkisneededtoexploreother geneticandepigeneticmechanismsatworkthatcould mimictheexpressionpatternsseeninTS.Avariety ofgenomicandproteomicapproachesshouldalsobe undertakentounderstandthegeneticsofTS(Hong etal.,2004;Tangetal.,2005). SWAINETAL. 950 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. EpigeneticFactors:PerinatalEvents,PsychosocialStress, Infection,andImmuneResponse Anumberofepigeneticfactorshavebeenimplicated inthepathogenesisofTSinadditiontopsychosocial stress,includinggestationalandperinatalinsults, exposuretoandrogens,heat,andfatigueaswellas postinfectiousautoimmunemechanisms.Forexample, perinatalhypoxic/ischemiceventsappeartoincreasethe riskofdevelopingTS(Burdetal.,1999;Khalifaand vonKnorring,2005;Whitakeretal.,1997).Onerecent retrospectivestudyaddedprenatalmaternalsmokingas ariskfactorforTS(Mathewsetal.,2006).Altering dopaminesignalingmaybeakeymediatorofepisodic ischemiceffects(Deckeretal.,2003). MalesexisariskfactorforTS.Althoughthiscould beunderstoodbygeneticmechanisms,frequentmale- to-maletransmissionswithinfamiliesappeartoruleout thepresenceofanX-linkedvulnerabilitygene.The increasedprevalenceofTSinmaleshasledtothe hypothesisthatthepresenceofandrogenicsteroids duringcriticalperiodsinfetaldevelopmentmayplaya roleinthelaterdevelopmentoftheillness(Peterson etal.,1998b).Observationofgender-relatedbehaviors (consistentwithelevatedprenatalandrogens)correlated withticseveritysupportsthisnotion(Alexanderand Peterson,2004).Althoughtheseeffectsmaybedueto androgenicsteroidsexpressedearlyindevelopment,itis likelythattherearesex-specificpatternsofgene expressioninmaleversusfemalebrainsthatinfluence theirdifferentiationandfunction(Dewingetal.,2006). PatientswithTSreporthigherlevelsofpsychosocial stress,andlatentclassmodelingofprospectivelong- itudinaldataindicatethatantecedentstressescan increasefutureticandOCsymptomseverity(Findley etal.,2003;Linetal.,2006).TheTSpatientsalsohave significantlyhigherlevelsofCSFcorticotrophin- releasingfactorthaneithernormalcontrolsor non Y tic-relatedOCDpatients.Althoughthefunctional significanceofthisfindingremainstobeelucidated, theseresultsareconsistentwiththehypothesisthat stress-relatedneurobiologicalmechanismsmayplaya roleinthepathobiologyofTS. Temperaturedysregulationinvolvingsomechangein hypothalamicfunctionhasalsobeenproposedasa factorinthepathobiologyofsomeindividualswithTS (Kessler,2002,2004).Inacaseseries(Scahilletal., 2001b)anincreaseinambienttemperature,aswellas corebodytemperature,wasassociatedwithatransient increaseinticsinsomepatients.Thisincreaseintics wascorrelatedwiththeirlocalsweatrateviaa dopamine-mediatedpathwayinthehypothalamus. Speculationconcerningapostinfectiousetiologyfor TSandOCDdatesfromthelate1800s(Kushner, 1999)andhasrecentlybecomeanintenseand controversialareaofresearch(Hoekstraetal.,2004a). ItiswellestablishedthatgroupA " -hemolytic streptococci(GABHS)cantriggerimmune-mediated diseaseingeneticallypredisposedindividuals.Rheu- maticfeverisadelayedsequelaofGABHS,occurring approximately3weeksfollowinganupperrespiratory tractinfection.Inflammatorylesionsinvolvingthe joints,heart,and/orCNScharacterizerheumaticfever. TheCNSmanifestationsarereferredtoasSC.In additiontochorea,someSCpatientsdisplaymotorand phonicticsaswellasOCandADHDsymptoms, suggestingthepossibilitythat,atleastinsome instances,thesedisordersshareacommonetiology (Maiaetal.,1999).Casereportshavealsoimplicated otherinfectiousprocessesinTSetiologyincluding Lymedisease(Riedeletal.,1998)and Mycoplasma pneumonia(Muller2004;Mulleretal.,2000). Swedoetal.(1998)proposedthatpediatricauto- immuneneuropsychiatricdisorderassociatedwith streptococcalinfection(PANDAS)representsadistinct clinicalentityandincludessomecasesofTSandOCD. InPANDASitispostulatedthatalthoughGABHSis theinitialautoimmunity-incitingevent,viruses,other bacteria,orevennoninfectiousimmunological responsesarecapableoftriggeringsubsequentsymptom exacerbationsviamolecularmimicry,suchthatanti- bodiesdirectedagainstGABHSattack(becauseofa similarstructure)cellsinthebrain(Sniderand Swedo,2004). ThestrongestevidencethatGABHSmaybe involvedintheonsetofTSandOCDcomesfrom therecentreportbyMelletal.(2005).Thisisacase- controlstudyof144children4to13yearsoldwho receivedtheirfirstdiagnosisofOCD,TS,ortic disorderbetweenJanuary1992andDecember1999. Caseswerematchedtocontrolsbybirthdate,sex, primaryphysician,andpropensitytoseekhealthcare. PatientswithOCD,TS,orticdisorderweremore likelythancontrolstohavehadstreptococcalinfection inthe3monthsbeforeonsetdate.Theriskwashigher amongchildrenwithmultiplestreptococcalinfections within12months.Indeed,havingmultipleinfections 10-YEARREVIEW:TOURETTESYNDROMEANDTICS 951 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. withgroupA " -hemolyticstreptococcuswithina12- monthperiodwasassociatedwithanincreasedriskof TSwithanoddsratioof13.6(95%confidenceinterval 1.93 Y 51.0). Incontrast,unselectedTScasesfollowedlong- itudinallyfor1year(Luoetal.,2004)indicatedno morethanachanceassociationbetweennewlyacquired GABHSinfectionsandticsymptomexacerbations. Similarly,inacase-controlstudyPerrinetal.(2004) foundlittleevidenceofincreasedticorOCsymptoms intheaftermathofwell-documented(andtreated) GABHSinfections,castingsomedoubtonthe hypothesis.Todate,treatmentsbasedonthemolecular mimicryhypothesishavebeennonspecific,theresults havebeeninconsistent(Hoekstraetal.,2004b; Perlmutteretal.,1999)andthedataconcerning antibioticprophylaxishavenotbeenparticularly compelling(Garveyetal.,1999;Snideretal.,2005). Theexactimmunologicalmechanismsinvolvedin TSremainindoubt.Molecularmimicry,altered cytokineproduction,andalteredimmunesuppression havebeenimplicated.Withregardtomolecular mimicry,severalgroupshavereportedincreasedtiters ofantistreptococcalantibodies(CardonaandOrefici, 2001;Churchetal.,2003;Mulleretal.,2001; Wendlandtetal.,2001),whereasothershavenot (Luoetal.,2004;Morshedetal.,2001;Singeretal., 1998).Therehavealsobeenanumberofstudies reportingthepresenceofantineuralantibodiesinthe serumofTSandOCDpatients(Morshedetal.,2001; Singeretal.,1998;Wendlandtetal.,2001). Basicresearchtodevelopananimalmodelandstudy themolecularmechanismsofPANDASusinganti- neuralantibodieshave,however,yieldedonlymixed results(Hallettetal.,2000;Hoffmanetal.,2004; Loiselleetal.,2003;Singeretal.,2005;Tayloretal., 2002).Inthemostpromisingstudytodate,Kirvan etal.(2003)demonstratedthatantibodiesproduced bya14-year-oldgirlwithSCspecificallyrecognizeda numberofneuronalligandsincludinglysoganglioside and N -acetyl- " - D -glucosamine.Moreimportant,these antibodieswerefoundtobindtothesurfaceofhuman neuronalcellsandtriggerthecalcium/calmodulin- dependentproteinkinaseIIcascade,suggestingthat SCmaybedueinparttoalterationsinintracellular signalingpathways.Thisfindinghasnowbeen replicatedinPANDAScases(Kirvanetal.,2006). Otherpromisingcandidatesformechanisticinvolve- mentinTSare ! -and + -enolase,aldolaseC,and pyruvatekinaseM1(Daleetal.,2005),althoughthese findingsarecontroversial(Singeretal.,2005). Recently,investigatorshavebeguntolookbeyondB cellmechanisms.Forexample,werecentlyreported thatcertainproinflammatorycytokines(tumornecrosis factor- ! andinterleukin-12)wereelevatedinTS patientscomparedwithcontrolsatbaselineandduring symptomexacerbation(Leckmanetal.,2005).Pre- liminarydataalsoindicatethatsomeTSsubjectsmay havedecreasednumbersofregulatoryTcells(Kawikova etal.,2007).Additionalprospectivelongitudinal studiesareneededtoexaminetherelationshipsbetween anarrayofimmunemodulatorsandTcellmechanisms. NEURALSUBSTRATESOFHABITFORMATION, MOTORCONTROL,ANDTICS Habitsareassembledroutinesthatlinksensorycues withmotoractionthroughaformofprocedural learning.Understandingtheneuralsubstratesofhabit formationandprocedurallearningmayleadtoabetter understandingofTS(CanalesandGraybiel,2000; LeckmanandRiddle,2000;Leckmanetal.,2006; Mink,2001).Althoughnodirectcausallinkbetween ticsandhabitshasbeenestablished,recentstudiesare showingdeficitsinprocedurallearning.Inastudyof20 childrenwithTScomparedwith20healthycontrols, Kerietal.(2002)showedadeficitintheprobabilistic classificationtaskthatwasmoresevereinasubsetwith moresevereticsymptoms.Inalargerstudyofmore than50childrenandadultswithTS,Marshetal. (2004)foundthatTSpatientshadimpairedhabit learningrelativetonormalcontrols.Furthermore,their acquisitionrateofthetaskactuallycorrelatedinversely withtheseverityofticsymptoms.Afollow-upreport (Marshetal.,2005)confirmedthedeficitinprobabi- listiclearningandalsofoundthatatestforanother subtypeofprocedurallearning,perceptualmotorskill learning,wasnotdifferentinTSsubjects.Thissuggests thatdifferentformsofprocedurallearningmaybe dissociableaccordingtoTSpathologyandseverityof symptoms.Inadditiontodifficultieswithprocedural learning,patientswithTShaveconsistentlyshown difficultieswithfinemotorcontrol,motorinhibition, andvisualmotorintegration(Crawfordetal.,2005; Mulleretal.,2003,Schultzetal.,1998).Perhapsthe moststrikingobservationistherecentfindingthat SWAINETAL. 952 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. poorerperformancewiththedominanthandonthe PurduePegboardtestduringchildhoodisassociated withworseadulthoodticseverity(Blochetal.,2006b). NeuralCircuitry Tomakeadvancesinunderstandingoftheclinical aspectsofTS,investigatorshavebeenstudyingthebasic braincircuitsthatunderlieprocedurallearning,habit formation,andinternallyandexternallyguidedmotor control.Progresshasbeenparticularlyremarkablein studyingthemultisynapticneuralcircuitsorloops thatlinkthecerebralcortexwithseveralsubcortical regions(GraybielandCanales,2001;Haber,2003; Haberetal.,2000;Jogetal.,1999;Middletonand Strick,2000).Keyaspectsofourunderstandingofthese neuronsandcircuitsareoutlinedbelow. BasicCircuitry. Corticalneuronsprojectingtothe striatumoutnumberstriatalmediumspinyneuronsby aboutafactorof10(ZhengandWilson,2002).These convergentcorticalefferentneuronsprojecttothe dendritesofmediumspinyneuronswithintwo structurallysimilarbutneurochemicallydistinctcom- partmentsinthestriatum:striosomesandmatrix.These twocompartmentsdifferbytheircorticalinputs,with thestriosomalmediumspinyprojectionneurons mainlyreceivingconvergentlimbicandprelimbic inputsandneuronsinthematrixmainlyreceiving convergentinputfromipsilateralprimarymotorand sensorymotorcorticesandcontralateralprimarymotor cortices(Leckman,2002;Mink,2006).Theresponseof particularmediumspinyprojectionneuronsinthe striatumispartlydependentonperceptualcuesthatare judgedsalient,sorewardingandaversivestimulican bothserveascues(CanalesandGraybiel,2000). Severalotherlessabundantstriatalcelltypes probablyhaveakeyroleinmodulatinghabitlearning, includingcholinergictonicallyactiveneurons(TANs) andfast-spikingGABAergicinterneurons(Gonzalez- Burgosetal.,2005;Jogetal.,1999).TANsaresensitive tosalientperceptualcuesbecausetheysignalthe networkswithinthecorticobasalganglialearning circuitswhenthesecuesarise.Specifically,theyare responsivetodopaminergicinputsfromthesubstantia nigra,andthesesignalsprobablyparticipateinthe calculationofperceivedsalience(rewardvalue)of perceptualcuesalongwithexcitatoryinputsfrom midlinethalamicnuclei.Althoughthedopamine neurons ` responsereflectsmismatchbetweenexpecta- tionandoutcome,theTANsareinvarianttoreward predictability(Morrisetal.,2004).Inaddition,TAN pairsaretypicallysynchronizedcomparedtoaminority ofdopamineneuronpairs.Itappearsthatthestriatal cholinergicanddopaminergicsystemscarrydistinct messagesbydifferentmeansthatcanbeintegrated differentlytoshapethebasalgangliaresponsesto reward-relatedevents(Morrisetal.,2004). Thefast-spikingspinyinterneuronsofthestriatum receivedirectcorticalinputspredominantlyfromlateral corticalregions,includingtheprimarymotorand somatosensorycortex,andtheyarehighlysensitiveto corticalactivityintheseregions.Theyarealsoknownto beelectricallycoupledviagapjunctionsthatconnect adjacentdendrites.Onceactivated,thesefast-spiking neuronscaninhibitmanynearbystriatalprojection neuronssynchronouslyviasynapsesoncellbodiesand proximaldendrites(KoosandTepper,1999).Thecha- racteristicelectrophysiologicalpropertiesofthestriatal fast-spikingneurons(i.e.,irregularburstingwithstable intraburstfrequencies)arereminiscentoftemporal patterningoftics(PetersonandLeckman,1998). NeuropathologicalFindings. Althoughneuropatholo- gicalstudiesofpostmortemTSbrainsarefew,arecent stereologicalstudyindicatesthatthereisamarked alterationinthenumberanddensityofGABAergic parvalbumin-positivecellsinbasalgangliastructures (Kalanithietal.,2005).Inthecaudatetherewasa greaterthan50%reductionintheGABAergicfast- spikinginterneuronsanda30%to40%reductionof thesesamecellsintheputamen.Thissamestudyfound areductionoftheGABAergicparvalbumin-positive projectionneuronsintheexternalsegmentglobus pallidusaswellasadramaticincrease�(120%)inthe numberandproportionofGABAergicprojection neuronsoftheinternalsegmentoftheglobuspallidus (GPi).Thesealterationsareconsistentwithadevelop- mentaldefectintangentialmigrationofsome GABAergicneurons.Furtherstudiesareneededto confirmandextendthesefindings,suchastowarda morecompleteunderstandingofhowthedifferent striatalinterneuronsareaffected,anddeterminehow alterationsinGABAergicinterneuronsandGPiprojec- tionneuronscouldleadtoaformofthalamocortical dysrhythmia(Leckmanetal.,2006;Llina ´ setal.,2005). VolumetricMagneticResonanceImaging(MRI). Volu- metricMRIstudiesofbasalgangliainindividuals withTSarelargelyconsistentwiththesepostmortem 10-YEARREVIEW:TOURETTESYNDROMEANDTICS 953 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. results.Inthelargeststudyofbasalgangliavolume involvingatotalof154subjectswithTSand130 healthycontrols,Petersonetal.(2003)founda significantdecreaseinthevolumeofthecaudate nucleusinboththechildandadultagegroups. However,theydidnotfindadifferenceinstriatum oracorrelationbetweensymptomseverityand caudatevolumesinthiscross-sectionalstudy,possibly becausetheirsampleconsistedofacombinationof childrenandadults.Blochetal.(2005)foundan inversecorrelationbetweencaudatevolumeinchild- hoodandticseverityinearlyadulthood.Inaddition, Blochetal.foundthatthecaudatevolumein childhoodcouldaccountforapproximatelyonefifth ofthevarianceinticseverityinearlyadulthood. Inthesamegroupofsubjects,thecerebrumsand ventricleswereisolatedandthenparcellatedinto subregionsusingstandar danatomicallandmarks. IndividualswithTSwerefoundtohavelargervolumes indorsalprefrontalregions,largervolumesinparieto- occipitalregions,andsmallerinferioroccipitalvolumes (Petersonetal.,2001b).Regionalcerebralvolumes weresignificantlyassociatedwiththeseverityoftic symptomsinorbitofrontal,midtemporal,andparieto- occipitalregions.Therealsoappearstobeage- dependentalterationsinthecross-sectionalareaofthe corpuscallosum.Specifically,Plessenetal.(2004) reportedadecreaseincorpuscallosumsizeinchildren aswellasanincreaseinsizeinadultswithTS, indicatingthatchangesinwhitemattertracksinthis disorder. Inaddition,Leeetal.(2005)usingvolumetricMRI methodstocomparethalamicvolumesin18treatment- na ¨ veboysversus16healthycontrolsubjectsfoundthat theTSsubjectshadsignificantlylargerleftthalamic volumesincomparisonwiththoseofhealthysubjects. Inanotherpreliminaryreport,Ludolphetal.(2006) recentlyshowedlocallyincreasedgray-mattervolumes bilaterallyintheventralputamen.Therewerealso regionaldecreasesingraymatterinthelefthippocam- palgyrus.Thesefindingsconfirmanassociation betweenstriatalabnormalitiesandTSandtheinvolve- mentoftemporolimbicpathwaysofthecorticostria- tothalamocorticalcircuits,butthesefindingsawait confirmationinalargerseries. Arecentstudyshowedthatachildhooddiagnosisof TS,OCD,orADHDsignificantlyincreasedthe likelihoodofdetectingcerebralhyperintensities,parti- cularlyinthesubcortex(Amatetal.,2006).This supportsthenotionthatsubcorticalinjury,perhapsdue toautoimmuneprocesses,mayplayaroleinthe pathophysiologyoftheseconditions.Clearly,more volumetricstudiesusingcomparablemethodsacrossall implicatedbrainregionsareneededtoclarifythebrain morphologyofTSandrelateddisorders,aswellasthe roleofimagingindiagnosisandtreatment. FunctionalBrainImaging. Thusfar,therehaveonly beenafewpublishedstudiesofTSusingfunctional MRI(fMRI),whichtakesadvantageofstate-dependent bloodoxygenationasameasureofbrainactivity.In adultswithTS,Petersonetal.(1998a)comparedbrain activityduringblocksoftime,duringwhichticswere voluntarilysuppressedornotsuppressed.Duringtic suppression,prefrontalcortical,thalamicandbasal gangliaareaswereactivated.Theseactivationswere inverselycorrelatedwithticseverity(i.e.,lessactivation wasassociatedwithhigherticseverity).Thisfinding suggeststhatagreaterabilityofbasalgangliatosuppress corticalactivitymaybelinkedwithdecreasedtic severityandisinagreementwithpositronemission tomographyandsingle-photonemissioncomputed tomographystudiesthatsuggestinvolvementofthe basalgangliainTS(GerardandPeterson,2003).Some investigatorshavesoughttoaltertheactivityofthe prefrontalareaswithmagneticfieldsinaneffortto enhancethevoluntarycontroloftics,withmixedresults (Georgeetal.,2001).InanotherfMRIstudySerrien etal.(2002)mappedbrainactivityduringmotortasks comparedtobaselineinthreecontrolandthreeTS patients.TSsubjectshadconsiderablyreducedactiva- tionsinpremotorandparietalcorticesaswellasthe basalgangliaandthalamus.Incontrasttothesestudies, Biswaletal.(1998)foundanincreaseinbrainactivity incorticalmotorareasduringvoluntarybimanual motortappingmovements,butthisstudyusedlow resolutionanddifferentanalysesforpatientsversus controls.Inapilotstudyusingaworkingmemorytask duringfMRI,Hersheyetal.(2004)comparedTS patientstocontrolsubjectsbothwithandwithout levodopainfusion.Theyobservedincreasedbrain activityinparietal,frontalcortical,andthalamicareas ofTSpatients,andtheincreasedactivitywasnormal- izedbylevodopa.Mostrecently,Bohlhalteretal. (2006)studiedtheneuralcorrelatesofticsand associatedurgesusinganevent-relatedfMRIprotocol. Onthebasisofsynchronizedvideo/audiorecordings, SWAINETAL. 954 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. fMRIactivitieswereanalyzed2secondsbeforeandat ticonset.Abrainnetworkofparalimbicareasin- cludingtheanteriorcingulateandinsularcortex, supplementarymotorarea,andparietaloperculumwas foundtobeactivatedbeforeticonset.Incontrast,at thebeginningofticaction,significantfMRIactivity wasfoundinsensorimotorareasincludingthesuperior parietallobulebilaterallyandthecerebellum.The resultsofthisstudyindicatethatparalimbicand sensoryassociationareasarecriticallyimplicatedintic generation. Investigatorshavealsoexaminedthecorrelationof metabolicactivityacrossvariousbrainregionsand foundthatchangesinthecouplingoftheputamenand ventralstriatumwithanumberofotherbrainregions differentiatedTSpatientsfromcontrols.Forexample, inpositionemissiontomographystudies,Jeffriesetal. (2002)notedareversalinthepatternofcorticostria- tothalamocorticalcircuitinteractionsinthemotorand lateralorbitofrontalcortices.Similarly,Sternetal. (2000)foundthatincreasedactivityinasetof neocortical,paralimbic,andsubcorticalregions (includingthesupplementarymotor,premotor,ante- riorcingulate,dorsolater al-rostralprefrontal,and primarymotorcortices;Broca ` sarea;insula;claustrum; putamen;andcaudate)werehighlycorrelatedwithtic behavior.Perhapsnotsurprising,intheonepatient withprominentcoprolalia,thevocalticswereasso- ciatedwithincreasedactivityintheprerolandicand postrolandiclanguageregions,insula,caudate,thala- mus,andcerebellum. DopamineModulation Aswithhabitsandstereotypies,ascendingdopami- nergicpathwayslikelyplayaroleintheconsolidation andperformanceoftics.Evidenceofabnormal dopamineneurotransmissioninTSisinferredfrom twoclinicalobservations.First,blockadeofdopamine receptorsbyneurolepticdrugssuppressesticsina majorityofpatients.Inaddition,dopamine-releasing drugsprecipitateorexacerbatetics(Scahilletal.,2006). Indeed,ithasbeenshownthatTSpatientsreleasemore dopamineinresponsetoamphetaminecomparedto normalcontrolsatdopaminergicsynapses(Singeretal., 2002).Second,theimportanceofdopamineinTSis supportedbybrainimagingusingsingle-photon emissioncomputedtomography.Severalinvestigators reportincreasedlevelsofdopaminergicinnervationof thestriatuminTSsubjectscomparedwithcontrols (Albinetal.,2003;Cheonetal.,2004;Mu ¨ ller-Vahl etal.,2000;Serra-Mestresetal.,2004).Inonetwin studyinvolvingfivepairs,ticseveritywasrelatedto dopamineD2receptorbindingintheheadofthe caudate(Wolfetal.,1996). Neurophysiology Noninvasiveinvivoneurophysiologicalresearchin TShasledtoseveralareasofsignificantprogress.The firstconcernstheuseofastartleparadigmtomeasure inhibitorydeficitsbymonitoringthereductionin startlereflexmagnitude.Swerdlowetal.(2001)have recentlyconfirmedandextendedearlierfindings indicatingthatTSpatientshavedeficitsinsensory gatingacrossanumberofsensorymodalities.Although prepulseinhibitionabnormalitieshavebeenobserved acrossavarietyofneuropsychiatricpopulationsinclud- ingschizophrenia,OCD,Huntington ` sdisease,noc- turnalenuresis,attention-deficitdisorder,Asperger ` s syndrome,andTS,perhapssomefinalcommon pathwaysmediateabnormalprepulseinhibitioninall ofthesediseases.WithrespecttoTS,thesedeficitsin inhibitorygatingareconsistentwiththeideathatthere issomediminishedabilitytoappropriatelymanageor ‘‘gate’’sensoryinputstomotorprograms,whichare releasedastics(Swerdlowetal.,2000).Asecond advancehasbeentheinvestigationofmotorsystem excitabilitybymeansofsingleandpairedpulse transcranialmagneticstimulation.Studiestodatein groupsofpatientswithTShaveindicatedthatthe corticalsilentperiod(aperiodofdecreasedexcitability followingstimulation)isshortenedinTS.This intracorticalexcitabilityisseenfrequentlyinchildren withADHDcomorbidwithaticdisorder(Molletal., 1999;Ziemannetal.,1997).Thisheightenedlevelof corticalexcitabilitymayberelatedtothepossible reductioninthenumberofGABAergicinterneuronsin thecortex(Kalanithietal.,2005).Thismayevenfit withrecentgeneticfindingsinsequencevariants involvedinthegenesthatregulatesaxonal-dendritic development(Abelsonetal.,2005). Third,Serrienetal.(2005)recentlyidentifiedsimilar sensorimotor-frontalconnectionsinvolvedintheacute suppressionofinvoluntaryticsasevidencedby increasedEEGcoherenceinthealphafrequencyband (8 Y 12Hz)rangeduringsuppressionofvoluntary movementsinindividualswithTScomparedwith 10-YEARREVIEW:TOURETTESYNDROMEANDTICS 955 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. healthysubjectsduringaGo-NoGotask.Thisfinding takenwiththefindingsfromthePetersonetal.(1998b) reportsuggestfairlyclearlythatthefrontallobesmay playanimportantcompensatoryroleinticsuppression andcoherenceinthealphabandmaybepartof thisprocess. Finally,thepreliminaryfindingsthatablation(or high-frequencystimulationusingdeepbrainelectrodes) inregionsoftheGPiand/orthemidlinethalamic nucleicanameliorateticsinsevere,persistentcasesof TS(Vandewalleetal.,1999)powerfullysupportthe viewthatelectrophysiologicalstudiesandinterventions holdpromisejustastheydofordisorderssuchas Parkinson ` sdisease. Prospectivelongitudinalstudieswithhigherresolu- tionwillbeneededtoexaminefullythedevelopmental processes,sexualdimorphisms,andpossibleeffectsof medicationoncriticalcellcompartments.Itwillalsobe importanttodeterminewhetheranyofthesevolu- metricandfunctionalfindingsarepredictiveoflater clinicaloutcomes.Thecombinationofimaging techniqueswithreal-timeneurophysiologicaltech- niques,suchaselectroencephalographyandmagne- toencephalography,mayhelptodeterminewhetherany brainimagingfindingsinTScontributetothe productionofticsorwhethertheyconstitutea compensatoryresponse(AlbinandMink,2006;Llinas etal.,2005;Segawa,2003). ASSESSMENT Accumulatedclinicalexperienceduringthepast10 yearsconfirmstheadagethatclinicalevaluationofthe childoradolescentwithTSproperlyconsidersthe B wholeperson, ^ possessedofarichpersonaland interpersonallife,notjustacollectionofabnormal motorsymptoms(CohenandLeckman,1999;Scahill etal.,2006).Intheprocessofacomprehensive evaluation,thefullrangeofdifficultiesandcompeten- ciesshouldbecharted.Acriticalquestionisthedegree towhichticsinterferewiththechild ` semotional,social, familial,andschoolexperiences.Todeterminethis,itis oftenusefultomonitorsymptomsoverafewmonthsto assesstheirseverityandfluctuation,impactonthe family,andthechild ` sandfamily ` sadaptation.This monitoringcanoftenbeaccomplishedwiththe family ` skeepingrecordsorusingstandardforms (Leckmanetal.,1999b). Althoughthedistressedfamilymayfocusonthe annoyingandsociallystigmatizingtics,itistheclini- cian ` sresponsibilitytoplacetheticsintotheproper contextofthechild ` soveralldevelopment.Bythetime ofevaluation,thechildmaybeupsetbyhisorher inabilitytocontroltheticsandbycriticismfrom parents,teachers,andpeerswhoexhorthimorherto controlhisorherstrangebehavior,whichtheymay believeheorshecancontrol.Centraltasksofevaluation includetheclarifyingandaddressingoffamilyissues, suchasparentalguiltandmisconceptions.Indeed, diagnosticevaluationiscloselyconnectedwiththefirst stepsoftreatment. ChildrenwithTStendtohavedifficultieswith attentionandpersistenceaswellasplanning,organiza- tion,andsocialproblemsolving(Channonetal.,2003; Crawfordetal.,2005;Mahoneetal.,2001;Ozonoff andJensen,1999;Yuenetal.,2005).Manyhavepoor penmanship(Schultzetal.,1998).Schoolworkmay alsobeimpairedbyavarietyofcompulsions,suchas theneedtoscratchoutwordsorreturntothebeginning ofasentence(Blochetal.,2006b).Psychologicaltesting isusefulifalearningdisabilityissuspected.Indeed,in databaseof5,450patientswithTS,1,235(22.7%)had learningdisabilities(Burdetal.,2005). Ticsaresudden,habit-likemovementsorutterances thattypicallymimicsomefragmentofnormalbehavior andinvolvediscretemusclegroups.Theneurological examinationofachildwithTSisthusofconsiderable value.Ticsmaybemistakenforakathisia,tardive dyskinesia,chorea,orotherhyperkineticmovement disorders(Jankovic,2001).Caseswithunusualhis- tories,co-occurringchangesinmentalstatus,or evidenceofseizuresshouldbeconsideredforreferral. Diagnosticcriteriaincommonuseincludethe InternationalClassificationofDiseaseandRelated HealthProblems,10threvision(WorldHealthOrga- nization,1998)andthe DSM-IV-TR .Althoughthere aresomecleardiscrepancies,thesemanualsarebroadly congruentwitheachother.Finally,tominimizeerrorin caseascertainmentandproduceaninstrumentmeasur- ingthelikelihoodofhavingTS,aninternationalteam ofexpertshasrecentlypublishedaTSDiagnostic ConfidenceIndex(Robertsonetal.,1999).Scoreson thisDiagnosticConfidenceIndexarehighlycorrelated withcurrentticseverity,asmeasuredbyapsychomet- ricallysoundandwidelyusedclinician-ratingscale,the YaleGlobalTicSeverityScale(Storchetal.,2005). SWAINETAL. 956 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. Acomprehensiveassessmentalsoincludesathor- oughperinatal,medical,developmentalfamily,and psychosocialhistoryalongwithscreeningforADHD, OCD,andlearningdifficulties.Explorationofthe child ` sstrengthsandabilitiesisworthwhilebecause theyareoftenoverlookedinthethroesofthediagnosis andoverfocusonthetics.ChildrenwithTSareoften anecdotallyobservedtobeparticularlyattunedtothe concernsandwell-beingofothers,possiblybecauseof theirownexperienceofillness(CohenandLeckman, 1999).Aswithallpediatricpsychiatriccare,evaluation anddocumentationofmedicalcarearenecessary, includingthedateofthelastphysicalexaminationand considerationoflaboratoryteststoruleoutanymedical conditionsincludinginfectionsorneurologicalcondi- tions.Thisisespeciallyimportantbeforestartingany medicationtreatment. TREATMENTOFTICS Despitesomeadvancesduringthepast10years,ideal antitictreatmentsarenotyetavailable.Thedecisionto begintreatmentisbasedonsymptomseverityinvolving thepresenceofatleastmoderatelysevereticsand evidencethattheticsareasignificantsourceof interferencewithdailylifeasreflectedinself-esteem, interpersonalrelationships(familymembers,peers,and teachers),andabilitytoperformuptoone ` spotentialin schoolsettings(Kingetal.,2003;SwainandLeckman, 2003).ManycasesofTSaremoretroublingtofamily membersthantheaffectedindividualandmaybe managedsuccessfullywithoutresortingtomedications. Additionally,becausethesymptomswaxandwanein severity,itoftenbesttoinitiatetreatmentwitheduca- tionalinterventionsandlifestyleadjustmentsbefore resortingtomedications(Leckmanetal.,1999b).In patientspresentingwithcomorbidADHD,OCD, depression,orbipolardisorder,itisadvisabletotreat thecomorbidconditionfirstbecausetreatmentofsuch disordersmaydiminishticseverity.Althoughathorough reviewoftheinterventionsforeachofthesedisordersis beyondthescopeofthisreview,someofthemostrecent studiesarementionedinpassing,andfurtherdetailsmay befoundelsewhere(Blochetal.,2006c;Castellanos etal.,1997;Martinetal.,2003;Scahilletal.,2006; TouretteSyndromeStudyGroup,2002). Medicationsforticsmustalsotakeintoaccountthe natural,idiosyncratic,andsometimesdramaticvaria- tionsinticseverity.Failuretodosomaysuggestan effectiveperiodofmedicationactionthatispurely coincidentalortemporarilymaskapotentiallyuseful treatment.Forexample,coincidentalremittanceoftic severityduetothenaturalhistoryoftheillnesswith initiationofamedicationmayconvincetheclinician andfamilythatamedicationwaseffective.Inanother case,naturalworseningofthesymptomsmayleadto reactiveandunnecessaryincreasesinmedicationand increasedriskofadverseeffects.Education,lifestyle adjustments,andwatchfulwaitingwithreminders aboutthewaxingandwaningcourseofTSareoften therightstrategyatfirst(Leckmanetal.,1999b). EducationalInterventions Withthesupportofadvocacygroupssuchasthe TouretteSyndromeAssociation,enhancedawareness aboutTSforfamilies,educators,andpeersmaypromote betterunderstandingandtolerance,whichcanhavea positiveinfluenceontheoverallcourseofillness (Leckmanetal.,1999b).Activecollaborationwiththe schoolisessentialtofacilitateappropriateclassroom managementandoptimalcurriculumplanning.Inmany cases,adviceregardingdisruptivebehaviorwarrants limit-settingandtoleranceofticbehaviors. DietandLifestyle Acuteandchronicstresscanexacerbatetics,so educationaboutthepotentialroleofstressinTSis warranted.Psychotherapymaybeusefultoimprove self-esteem,socialcoping,familystrain,andschool adjustment,butitisunclearwhethertheydirectlyaffect ticseverity.Regularappointmentswiththesame clinicalteamwhocanhelpthepatientdealwiththe changingmanifestationsofthedisorderthroughthe yearsisoptimalwhenpossible.Regularcontactvia telephoneore-mailmayalsobehelpful.Participation inregularschoolandextracurricularactivitiesis encouragedtooffsetpotentialoverprotection.No specificdietisknowntobeofparticularbenefit, althoughabalanced,healthydietmaycontributeto overallwell-beingandstressreduction(Manteletal., 2004).Caffeineshouldbeminimizedbecauseitmay exacerbateticsinsomechildren(DavisandOsorio, 1998).Theimpactofphysicalexerciseonticsymptoms hasnotbeensystematicallystudied,althougharegular programofexercisecanbebeneficialasastress- managementstrategy,toenhancethechild ` ssense 10-YEARREVIEW:TOURETTESYNDROMEANDTICS 957 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. ofmastery,andcontributetooverallwell-being (Hollenbeck,2001;LeckmanandCohen,1999). BehavioralTherapy Awiderangeofbehavioralinterventionshasbeen appliedtothetreatmentofticswithunconvincing resultsinmostinstances(Kingetal.,1999).For example,techniquessuchasnegativepracticeandmass practicearenoteffectiveandhavenoplaceinthe treatmentoftics(PiacentiniandChang,2001).Single casestudies,threepilotrandomizedclinicaltrials,one inchildren(PiacentiniandChang,2001),twoinadults (Deckersbachetal.,2006;Wilhelmetal.,2003),and onespanningages7to55(Verdellenetal.,2004), providepromisingresultsforhabit-reversaltraining (HRT).TheactiveingredientsofHRTarepresumedto beawarenesstrainingandcompetingresponsetraining. Awarenesstrainingattemptstoidentifythesituationsin whichticsoccuraswellasthebeginningofaticorbout oftics.Onceidentified,thepatientiscoachedto imposeavoluntarycompetingmovementincompatible withthetic.Asyet,HRTisnotyetaprovenandwidely practicedtreatment.Twolarge-scaleclinicaltrialsare nowunderway,oneinchildrenandoneinadults. Thesetrialsshouldprovidedefinitiveinformationon theefficacyofHRTforTSandassociatedconditions. Cognitive-behavioraltreatmentssuchasexposure andresponsepreventioncontinuetobeamainstayfor thetreatmentofOCD,especiallywhenthereis significantanxietyorphobicavoidance(Pediatric OCDTreatmentStudy,2004).Althoughadding psychosocialtherapytomethylphenidatemaynot improveitseffectivenessinstimulant-responsivechil- drenwithADHD(Scahill,2005),parenttraining (Kazdin,2003)andangermanagement(Sukhodolsky etal.,2004)fordisruptivebehaviorinchildrenand adolescentswithTSmayalsobehelpful.Althoughnot rigorouslysupportedbycontrolledresearch,other formaldynamicinterpersonalorsupportivepsy- chotherapeuticinterventionsmayfacilitatenormal developmentaltasksoffriendshipdevelopment, improvedschooladjustment,coherentpersonality formation,andday-to-daystressmanagement. PharmacologicalTreatmentofTics Despitethelackofanidealantiticmedication, severalmedicationshavedemonstratedefficacy(Scahill etal.,2006)and,withdueattentiontopossibleside effects,maybepartofatreatmentplan(Table1). Pharmacologicaltreatmentmaybestartedwithlow dosesof ! -adrenergicdrugs,whichhaveshowneffect sizes�0.5indouble-blind,placebo-controlledstudies (Scahilletal.,2001a;TouretteSyndromeStudyGroup, 2002).Clonidineprimarilyactivatespresynapticauto- receptorsinthelocusceruleustoreducenorepinephrine releaseandturnoverinthecerebralcortex.Reduced levelsofnorepinephrineinthethalamusmayberespon- sibleforthecommonlyreportedsedationwiththese medications.Startingat0.05mg/daywithgradual increasesonathreeorfourtimesperdayscheduletothe targetdosesof0.2to0.3mg/dayisrecommended (TouretteSyndromeStudyGroup,2002).Transdermal patchesofclonidinearenowavailablebuthavenotbeen wellstudied.Another ! -adrenergicagonistwithless sedationisguanfacine.Animalstudiesindicatethat guanfacineactivatespostsynapticprefrontal ! -adrenergic corticalreceptors,andbasedonthismechanism,itis believedtoimproveimpulsivity,attention,andworking memory(Averyetal.,2000).Guanfacinecanbestarted TABLE1 DrugsUsedintheTreatmentofTics:EmpiricSupport andDosingGuidelines Medication Empiric Support Starting Dose,mg UsualDose Range, mg/day Nonantipsychotics ClonidineB0.025 Y 0.050.2 Y 0.4 GuanficineB0.5 Y 12 Y 4 PergolideB0.025every2days0.15 Y 0.45 BotulinumtoxinABMotortics:50 Y 75U Vocaltics:1 Y 2.5U 75 Y 250 1 Y 2.5 Antipsychotics HaloperidolA0.25 Y 0.51.0 Y 4.0 PimozideA0.5 Y 12 Y 8 RisperidoneA0.25 Y 0.51 Y 3.5 FluphenazineB0.5 Y 1.01.5 Y 10 TiaprideB50 Y 150150 Y 500 ZiprasidoneB5 Y 1010 Y 80 Note: Toguideclinicalpractice,themedicationsusedforTSare classifiedaccordingtothelevelofempiricalsupport.Theabove criteriafromtheInternationalPsychopharmacologyAlgorithm Projectwereselected(Scahilletal.,2006):categoryAreflects treatmentswithgoodsupportiveevidenceofshort-termsafetyand efficacyderivedfromatleasttworandomizedplacebo-controlled trialswithpositiveresults;categoryBcorrespondstotreatments withfairsupportivedataasevidencedbyatleastonepositive placebo-controlledstudy. SWAINETAL. 958 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. at0.5mgatbedtime,withgraduallyincreasingdoseson atwice-dailyschedule.Thetargetdoseforthelonger actingguanfacineis1.5to4mg/day(Scahilletal., 2001a).Sideeffectsincludesedationandmid-sleep waking,whichcanoftenbeminimizedbyadjustingthe doseschedule.Othersideeffectsincludeconstipation, hypotension,andevensyncopeinrarecases(Kingetal., 2006),sobloodpressureandpulseshouldbemonitored, especiallyearlyintreatment. Althoughclonidineandguanfacinehavealsobeen showntobeeffectiveintreatingADHDsymptoms, whicharecomorbidwithTS,indouble-blindplacebo- controlledstudies(Scahilletal.,2001a;Tourette SyndromeStudyGroup,20 02),psychostimulants includingmethylphenidate, d -amphetamine,mixtures of d -and l -amphetamine,andatomoxetineareoften moreefficacious(Allenetal.,2005;Castellanosetal., 1997;Gadowetal.,1999;TouretteSyndromeStudy Group,2002). Antipsychoticshavealonghistoryofuseagainsttics witheffectsizesfortreatingticsofatleast0.6(Swain andLeckman,2003).Theyarethoughttoactprimarily byblockingdopaminereceptorsandtherebydecreasing dopaminergicinputfromthesubstantianigraand ventraltegmentumtothebasalganglia.Ofthetypical antipsychotics,haloperidolandpimozidehavebeenthe beststudied,withdouble-blind,controlledstudiesto supportthem(Salleeetal.,1997).Allofthese medications,however,areassociatedwithsignificant sideeffectsincludingacutedystonicreactions;oculo- gyriccrises;torticollis;drug-inducedparkinsonism; akathisia;socialphobia;weightgain;sedation;lossof drive,energy,andpersonality;drymouth;blurred vision;galactorrhea;gynecomastia;constipation;uri- naryretention;andelectrocardiographicchanges includingtachycardia,andtardivedyskinesia(Martin etal.,2003).Thus,if ! -adrenergicmedicationshave beentriedandfoundineffective,theatypicalanti- psychoticsareusuallythenextclassofmedicationsto consider.Atypicalantipsychoticsblockdopamineand serotoninreceptors.Thisdualpharmacologicalaction appearstobeprotectiveagainsttheneurologicaladverse effectsassociatedwithtypicalantipsychotics,suchas haloperidolandpimozide,whichareprimarilydopa- mineblockers.Followingapromisingopentrialwith risperidonefortics(BruunandBudman,1996),four randomizedcontrolledtrialshaveshowedthatrisperi- donewassuperiortoplacebo(Bruggemanetal.,2001; Dionetal.,2002;Gaffneyetal.,2002;Scahilletal., 2003).Twoofthesestudieshaveshownthatrisper- idonewasequallyaseffectiveaspimozide(Bruggeman etal.,2001;Gaffneyetal.,2002).Dosesrangingfrom 1.0to3.5mg/daywereeffective,andneurologicalside effectswererare.Themostcommonadverseeffects wereweightgain,lipidmetabolismabnormalities, sedation,andsleepdisturbance;socialphobiaand erectiledysfunctionoccurredinafewpatients.Todate, thereisonlyoneplacebo-controlledtrialwithziprasi- done(Salleeetal.,2000).Thisstudyshowed ziprasidonetobevirtuallyidenticaltorisperidonefor ticreduction.Althoughdatainpediatricpopulations arescarce,ziprasidonedoesnotappeartohavealower riskofweightgain(McDougleetal.,2002)compared withrisperidone(Scahilletal.,2003)andolanzapine (Maloneetal.,2001).Concernaboutthepotentialfor ziprasidonetoaltercardiacconduction,especiallyQTc prolongation,remains.Inaseriesofpediatricpatients withvariousdisorders,Blairetal.(2005)indicatethat anelectrocardiogramshouldbeobtainedatfourtime points:baseline,duringdoseadjustment,atmainte- nancedose,andannuallythereafter.Electrocardio- gramsarenotrequiredforatypicalantipsychoticsunless thereisapositivecardiachistoryinthepatient.Recent guidelinessuggestthatpatientsshouldbescreenedat baselinewithalipidpanelandfastingglucose(Martin etal.,2003).Theselaboratorytestsshouldberepeated atmaintenancedoseandrepeatedannuallythereafter. Weightanddietshouldalsobemonitored. Todate,theuseofolanzapineforticsissupportedby minimaldata:threeopen-labeltrials(Budmanetal., 2001;Stamenkovicetal.,2000;Stephensetal.,2004) andonecontrolledstudy(Onofrjetal.,2000)withonly foursubjects.However,untilmoredataareavailable,it shouldnotbeconsideredafirst-orsecond-linetreat- mentoption. OtherantipsychoticsthathavebeenusedinEurope butthatarenotavailableintheUnitedStatesinclude tiaprideandsulpiride.Pergolideisamixeddopamine agonistusedinParkinson ` sdisease,whichinlower dosesisthoughttohaveagreatereffectonpresynaptic autoreceptorsandleadtodecreaseddopaminerelease. Pergolidehasbeenevaluatedinopen-labelandplacebo- controlledtrials(Gilbertetal.,2000;2003;Lipinski etal.,1997).Theseresultssuggestthatpergolidehas apositivebutmoderateeffectontics.Adverseeffects includenausea,syncope,sedation,anddizziness. 10-YEARREVIEW:TOURETTESYNDROMEANDTICS 959 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. Thisagentmaybeespeciallyusefulifachildpresents withcomorbidrestlesslegssyndrome. Onlysmall,open-labelpilotstudiesareavailablefor medicationssuchasaripirazole,tetrabenazine,and benzodiazepines.Ariprazoleisanovelantipsychotic withantidopaminergicpropertiesthathasbeeneffec- tiveandtolerableinafewcaseseries(Bubletal.,2006; Kastrupetal.,2005;Padalaetal.,2005),butcontrolled studiesareneededbeforerecommendationsarepossi- ble.Tetrabenazineisanonantipsychoticdopamine antagonist,approvedasaninvestigationaldrug.Avail- abledatasuggestthattetrabenazinemaybeuseful,but morestudyisneeded(Sandor,2003).Thebenzodia- zepines,suchasclonazepam,areusedasanxiolyticsand occasionallyusedasanadjunctivetreatmentfortics, althoughithasnotbeenwellstudied.Giventhese drawbacks,especiallydisinhibitionanddependence, clonazepamisnotusedwidelyinTS. Acollectionofagentshasbeentestedduringthepast 10yearsinlargelysmall,open-labelpilotchallenge studieswithequivocalresultsfortreatingTS.Among theseagentsaresuchcalciumchannelantagonistsas donepezil(Hoopes,1999),dopaminergicmodulators selegiline(Feiginetal.,1996),levodopa(Blackand Mink,2000),odansetron(Torenetal.,1999,2005), ropinirole(Ancaetal.,2004),andmetaclopromide (Nicolsonetal.,2005);thehormonalmodulators flutamide(Petersonetal.,1998b)andcyproterone (IzmirandDursun,1999);theantiepilepticdrugs topiramate(AbuzzahabandBrown,2001)andlevetir- acetam(Awaadetal.,2005);theanti-inflammatory celecoxib(Muller,2004); andvariousnutritional supplements(Manteletal.,2004).However,dataon thesafetyandefficacyoftheseagentsarelimited. Furthersystematicstudyisneeded,especiallyin children,beforethesecanberecommendedforthe treatmentoftics. TheGABAergicmusclerelaxantbaclofenhasbeen showntoimproveticsinonelargeopentrial,although itlackedbaselineorfollow-upscores(Awaad,1999).In theonesmalldouble-blindplacebo-controlledcross- overstudy(Singeretal.,2001),baclofenwasnobetter thanplaceboinreducingticseverityinchildren. Nicotinechewinggumandpatcheshavealsobeenused totreattics.Inopentrialsencouragingeffectsof nicotineonticswerereported(Silveretal.,2001a). However,intheonlyplacebo-controlledtrialtherewas littleevidenceofbeneficialeffectsontics(Silveretal., 2001b).Inthatstudythenicotinepatchoraplacebo patchwasaddedtoongoingtreatmentwithhaloper- idol.Therewasnoenduringbenefitonticsafterthe additionofthepatch.Thenicotineantagonist mecamylaminehasbeentestedagainsttics.Apromising initialretrospectivecasestudy(Sanbergetal.,1998was againcounteredbyadouble-blind,placebo-controlled studythatfailedtofindsignificanteffects(Silveretal., 2001c.Theabsenceofbenefitandtheriskofnausea andvomitinglimittheusefulnessofnicotinicdrugsto treatTS. Botulinumtoxininjectionintodiscretemuscle groupshasbeenshowntobeeffectiveinopenand placebo-controlledtrials(Kwaketal.,2000;Marras etal.,2001),includingphonictics(Portaetal.,2004). Thesedatasuggestthatbotulinumtoxinmaybemost usefulforsinglebothersomedystonias.Botulinum toxinblocksacetylcholinereleaseattheneuromuscular junctionandproducesareversibleandtemporary reductioninmuscleactivity,whichmaylastweeksto monthsfordystonictics.Mainsideeffectsinclude sorenessattheinjectionsite,muscleweakness,ptosisif injectedforeyeblinking,andtransientdysphagiaif injectedintothelarynx. Severalmedicationshavebeenshowntobeineffec- tiveforthetreatmentofticdisorders.Forexample, thereisnoevidencethatselectiveserotoninreuptake inhibitorsareeffectiveinsuppressingtics.However, selectiveserotoninreuptakeinhibitortreatmentfor pediatricOCDiswellsupportedbyclinicaltrialsand manyTSpatientshavecomorbidOCD(Pediatric OCDTreatmentStudyTeam,2004).Unfortunately, manypatientswithOCDandacoexistingticdisorder respondlesswelltoselectiveserotoninreuptake inhibitorsandmayrequiretheadditionofsmalldoses ofaneurolepticoranatypicalneurolepticsuchas risperidone,whichincreasestheresponsetoselective serotoninreuptakeinhibitors(Blochetal.,2006c). OtherEmerging/ExperimentalTherapies InaccordancewiththetheorythatasubtypeofTS, characterizedbyabruptonsetandco-occurring GABHSinfection,maybetheresultofanautoimmune process,immunetherapieshavebeenexaminedwith inconsistentresults.Forexample,Perlmutteretal. (1999)foundthatintravenousgammaglobulinwas effectiveinreducingticandOCDsymptoms,although Hoekstraetal.(2004b)reachedoppositeconclusions SWAINETAL. 960 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. afterevaluatingtheirdata.Atpresent,theclinicianis simplyencouragedtobevigilantinassessingchildren withpharyngitisorthoseexposedtostreptococcusand tovigorouslytreatwithantibioticsifthereisapositive throatculture.Plasmapheresis,intravenousimmuno- globulin,orcorticosteroidsareexperimentaltreatments understudy,butareofuncertainbenefitatthispoint (Tuckeretal.,1996.Theyshouldonlybeundertaken withexpertsinthecontextofaformalresearchstudy. Withcertainunambiguousandsuddenticonset associatedwithstreptococcalinfection,antibiotictreat- menthasbeenoccasionallyremarkablyeffective;but again,antibodytreatmentisonlywarrantedwhenthere isclearevidenceofstreptococcalinfection. Transcranialmagneticstimulationisanewtechnol- ogyinwhichabrief,powerfulmagneticfieldis generatedbyasmallcoilpositionedovertheskull andwhichinducesanelectricalcurrentinthebrain. Suchnoninvasivebrainstimulationmayeffectlong- termchangesincorticalexcitability,whichmaybe abnormalinTS(Georgeetal.,2001).Thisisstillan experimentaltherapythetherapeuticstimulationparam- etersofwhichareunknown.However,arecentpilot studysuggeststhatthetreatmentissafeandwarrants furtherstudy(Chaeetal.,2004). Theresultsofneurosurgicalproceduresreinforcethe functionalimportanceofthalamicregionsthatarepart ofthecortical-subcorticalloops(Ackermansetal., 2006;Vandewalleetal.,1999).In1999Vandewalle etal.introducedtheuseofdeepbrainstimulationasa newapproachforintractableTS.Todate,several patientshaveundergonebilateralthalamicstimulation withpromisingresultsonticsandassociatedbehavioral disorders(Ackermansetal.,2006;Minketal.,2006). In2002bilateralstimulationoftheposteroventralGPi wasperformedinapatientwithrefractoryTS(vander Lindenetal.,2002).Therationaleforthechoiceofthis targetwasthepositiveeffectofGPistimulationon hyperkinesiasinParkinson ` sdisease.Mostrecently, twopatientswithsevereTShadbilateralelectrodes placedinthemidlinethalamicnucleiandintheGPi (Ackermansetal.,2006).Inthesetwopatients,both targetswereeffectiveinreducingtics.Insum,asin othermovementdisorders,adeeperunderstandingof thecircuitryinvolvedinTSmayleadtospecificcircuit- basedtherapiesusingdeep-brainstimulationtotreat refractorycases(Visser-Vandewalleetal.,2003,2004). However,becauseTSoftenspontaneouslyresolvesby adolescence,surgicalinterventionshouldbeviewedas anextraordinarystepandonlyconsideredinthemost severeandrefractorycasesthatinterferewithfunction andpersistintoadulthood. FUTUREPERSPECTIVES Animalandhumanstudiesofhabits,tics,and stereotypieshaveadvancedinbreadth,sophistication, andscopeduringthepastdecade.Thenumberof groupsengagedinthisworkhasgrowntoapointwhere acriticalmassofinvestigatorsispoisedtomake significantnewcontributionstoourunderstandingof thesebehaviors.Despiteenormousprogress,the complexityofthesesystemsinprimatesandhumans isformidable(Holtetal.,1997).Thekeyissueishow todisentangletheelaborateinteractionsbetween regionsofthefrontalcortexandthebasalgangliaand howtheseinteractionsactinconcerttolearnandset motor,emotive,andcognitiveactionplans.Joint venturesthatcombinetheeffortsofinvestigatorsat theleadingedgeofgenetics,neuroimmunology,and theneurosciences(molecular,neuralnetwork,devel- opmental,behavioral)withclinicalscholarsareneeded tosustainandaccelerateprogressinthisfield. Mostoftheavailableevidenceindicatesthat corticostriatothalamocorticalcircuitsarecrucialfor thedevelopmentofhabitsaswellasticsandrepetitive movements.Despitethisconvergence,theprecise mechanismsinvolvedremainindoubt.Whydotics appearwhentheydo?Whydotheywaxandwane?Why dotheyreachaworst-everpointinearlyadolescencefor themajorityandbecomeevenmoresevereinadulthood foranunluckyfew?Thesedevelopmentalissuesare likelycrucialforafullunderstandingofticdisorders.In ourview,adeterminedefforttoexploretheelectro- physiologyofthisdisorderusingEEGandmagnetoen- cephalographicrecordi ngsisournextbeststep (Leckmanetal.,2006;Llinasetal.,2005). Themonoaminergicsystemscontinuetobemajor areasoffocusbecausetheyhavebeenrepeatedly implicatedinhighlydiversebehavioralandcognitive functionsincludinghabitformation,theinductionof stereotypies,andtreatmentoftics.Specifically,mid- braindopaminergicneuronsplayacentralrolein motorcontrolandattentionalprocessesbymeansof directconnectionstothestriatumandprefrontal cortex,respectively.Understandingthetimingand 10-YEARREVIEW:TOURETTESYNDROMEANDTICS 961 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. maturationofthedopaminergicsystemandtheroleit playsinthegrowth,differentiation,andplasticityofthe CNSmayshedlightoncriticalwindowsofvulner- abilityinthedevelopmentandtimingoftics(Dewing etal.,2006). NeuralontogenyoftheGABAergicsystemsisalsoan intriguingareaofstudygermanetounderstanding movementdisordersandthesuspectedroleoffaulty inhibitorycircuitry.ManysuchinhibitoryGABAergic interneuronsofthecerebralcortexmigratetangentially fromthesameembryonicregionsintheganglionic eminencethatalsogiverisetotheGABAergicfast- spikinginterneuronsofthestriatum(Xuetal.,2003). Anappealinghypothesisisthatadverseeventsthatarise atspecificdevelopmentalpointsimpairtheappropriate migrationandmaturationofthesecellsandtheir assemblyintoinhibitorymotorcontrolcircuits.This couldaccountfortheimbalances,deficits,and disorganizationoffunctionofcellgroupsinthe striatumandcortex,leadingtodeficitsinmovement inhibitionhypothesizedtooccurinsomepatientswith TS.Furthermore,giventhemultipleafferentsystems andintegrationofsensorimotorandlimbicinformation inthebasalganglia,thispromisestobearichareaof study.Byunderstandingmolecularswitchesinvolvedin cellfate,proliferation,migration,anddeath,itmaybe possibletodesigntherapeuticinterventionstohaltor reversepotentiallyneurotoxiceventsbeforethemani- festationofanysymptoms. Theapplicationofcomputationalneuralnetworks mayalsogreatlyconfirmordismantlepresenttheories abouttheetiologyofticdisorders.Dynamiccomputer simulationsofneuroanatomicalandneurochemical circuitrymayonedayleadtoagreaterunderstandingof thebrain Y behaviorinterface.Suchmodelsarealready beingappliedtothestudyofprefrontalcortical-basal gangliacircuitryasitrelatestobothmotorand cognitiveinformationprocessing(Franketal.,2001). Forexample,modelingoftonicandphasicdopami- nergicactivity,perhapsasmediatedbyD1andD2 receptorsinthestriatumandprefrontalcortex, respectively,maybepromising.Thesetonicinputs maystabilizerepresentationsbyincreasingthesignal- to-noiseratioofbackgroundversusevokedprefrontal cortexactivity,whereastonicinputsmaysignalwhen newinputsshouldbeencodedoroldrepresentations shouldbeupdatedinresponsetosalient,reward- predictinginformation(Cohenetal.,2002).Asnew dataregardingdifferentcorticalregionsareincorpo- rated,futuremodelsmayprovidetestablehypothesesof howdifferencesormanipulationsofgenetics,circuit organization,andpharmacologymayleadtoadis- orderedorcuredphenotype. Inreviewingtheprogressduringthepastdecade severalcaveatsmustbekeptinmind.First,theremaybe neurobiologicalconsequencesofhavingtics.Second, theactofsuppressingticsmayaffectregionalactivityin thebrain.Inotherwords,thecontextualmentalstateof theindividualatthetimeofastudymayaffectthe measurementofinterest.Inthefuture,wecan anticipatethedeploymentofadvancedtechnologies (MRspectroscopy,diffusiontensorimaging,near- infraredopticalspectroscopy,andasyetunknown techniques)andthecombinationofbehavioralor neurophysiologicalstimuli(singleorpairedpulse transcranialmagneticbrainstimulationandstudiesof prepulseinhibitionandstartlereflexes)withinthe confinesofbrainimagingdevices.Thesemaneuverswill likelyyieldvaluabledatatoidentifymeaningful endophenotypesforfuturegeneticstudies.Longitudi- nalstudiesareneededtoaddressquestionsofriskand resilience,andideallythesewouldinvolvesubjectsat highgeneticriskwhohaveyettodisplaythe characteristicsymptomsofTS.Likewise,thedevelop- mentofvalidanimalorneurocomputationalmodels wouldbeamajorstepforward. Despiteouradvances,thereisnoidealantitic pharmacotherapy.Resultsarehighlyvariableand unfortunatelyoftenassociatedwithaheavyside-effect burden.However,novelpsychotropicsarecontinually appearing,eachwithadifferentarrayofcellularand subcellulartargets.Itishopedthatconverging pharmacologicalandneuropathologicalresearchwill findmedicationsthatarebothhighlyeffectiveandhave minimalsideeffects.Behavioralinterventionsunder studymayprovidenewapproachestothetreatmentof ticsandadaptivebehaviorpatternsinTS. Disclosure:Dr.ScahillisaconsultanttoJanssen,Pfizer,andBristol- MyersSquibb.Theotherauthorshavenofinancialrelationships todisclose. REFERENCES AbelsonJF,KwanKY,O ` RoakBJetal.(2005),Sequencevariantsin SLITRK1areassociatedwithTourette ` ssyndrome. Science 310:317 Y 320 SWAINETAL. 962 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007 Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited. 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Grossoehme,BCC,MDiv,JudithR.Ragsdale,MDiv,ChristineL.McHenry,MD,MATS,CeliaThurston,DMin,Thomas DeWitt,MD,LarryVandeCreek,BCC,DMin Objective: Theliteraturesuggeststhatamajorityofpediatriciansbelievethatspiritualityandreligionarerelevantinclinicalpractice, butonlyaminoritygivesthemattention.Thisprojectexploredthisdisparitybyrelatingpersonal/professionalcharacteristicsof pediatricianstothefrequencywithwhichtheygiveattentiontospiritualityandreligion. Methods: Pediatricians( N =737)associated with3academicMidwesternpediatrichospitalsrespondedtoasurveythatrequestedinformationconcerningthefrequencywith whichthey(1)talkedwithpatients/familiesabouttheirspiritualandreligiousconcernsand(2)participatedwiththeminspiritualor religiouspractices(eg,prayer).Theassociationsbetweenthesedataand10personalandprofessionalcharacteristicswereexamined. Results: Theresultsdemonstratedthedisparity,andtheanalysisidentified9pediatriciancharacteristicsthatweresignificantly associatedwithmorefrequentlytalkingwithpatients/familiesabouttheirspiritualandreligiousconcerns.Thecharacteristics includedincreasedage;aChristianreligiousheritage;self-descriptionasreligious;self-descriptionasspiritual;theimportanceof one ` sownspiritualityandreligioninclinicalpractice;thebeliefthatthespiritualityandreligionofpatients/familiesarerelevantin clinicalpractice;formalinstructionconcerningtheroleofspiritualityandreligioninhealthcare;relativecomfortaskingabout beliefs;andrelativecomfortaskingaboutpractices.Allofthesecharacteristicsexceptpediatricianagewerealsosignificantly associatedwiththeincreasedfrequencyofparticipationinspiritualandreligiouspracticeswithpatients/families. Conclusions: Attentiontospiritualandreligiousconcernsandpracticesareassociatedwithawebofpersonalandprofessionalpediatrician characteristics.Somecharacteristicspertaintothephysician ` spersonalinvestmentinspiritualityandreligionintheirownlives,and othersincludebeinguncomfortablewithspiritualandreligiousconcernsandpractices.Theseassociationsshedlightonthedisparity betweenacknowledgedspiritualityandreligionrelevancyandinattentiontoitinclinicalpractice. Pediatrics 2007;119:e117 Y e123. SWAINETAL. 968 J.AM.ACAD.CHILDADOLESC.PSYCHIATRY,46:8,AUGUST2007