Advances in the Neurochemistry and Neuropharmacology of Tourette Syndrome

552 Pages·2013·8.275 MB·2-551\552

by  Davide Martino and Andrea E. Cavanna (Eds.)

INTERNATIONAL
REVIEW OF
NEUROBIOLOGY
VOLUME112
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R. ADRON HARRIS
WaggonerCenterforAlcohol andDrugAddictionResearch
The University of Texas at Austin
Austin, Texas, USA
PETER JENNER
Division of Pharmacology and Therapeutics
GKT School of Biomedical Sciences
King's College, London, UK
EDITORIAL BOARD
ERICAAMODT HUDAAKIL
PHILIPPEASCHER MATTHEWJ.DURING
DONARDS.DWYER DAVIDFINK
MARTINGIURFA BARRYHALLIWELL
PAULGREENGARD JONKAAS
NOBUHATTORI LEAHKRUBITZER
DARCYKELLEY KEVINMCNAUGHT
BEAULOTTO JOSÉA.OBESO
MICAELAMORELLI CATHYJ.PRICE
JUDITHPRATT SOLOMONH.SNYDER
EVANSNYDER STEPHENG.WAXMAN
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CONTRIBUTORS
UmbertoBalottin
DepartmentofChildNeurologyandPsychiatry,IRCCS“C.Mondino”Foundation,
UniversityofPavia,Pavia,Italy
JudithBuse
DepartmentofChildandAdolescentPsychiatry,UniversityMedicalCenter,Technische
Univerita¨tDresden,Dresden,Germany
FrancescoCardona
DepartmentofPediatricsandChildNeuropsychiatry,SapienzaUniversityofRome,Rome,
Italy
AndreaE.Cavanna
MichaelTrimbleNeuropsychiatryResearchGroup,DepartmentofNeuropsychiatry,
BSMHFTandUniversityofBirmingham,Birmingham;SchoolofLifeandHealthSciences,
AstonUniversity,Birmingham,andSobellDepartmentofMotorNeuroscienceand
MovementDisorders,UCLandInstituteofNeurology,London,UnitedKingdom
StefanEhrlich
DepartmentofChildandAdolescentPsychiatry,UniversityMedicalCenter,Technische
Univerita¨tDresden,Dresden,Germany
ThomasV.Fernandez
ChildStudyCenter,YaleUniversitySchoolofMedicine,NewHaven,Connecticut,USA
MariangelaGulisano
DepartmentofMedicalandPediatricSciences,CataniaUniversity,Catania,Italy
AndreasHartmann
CentredeRe´fe´renceNationalMaladieRare:‘SyndromeGillesdelaTourette’,De´partement
deNeurologie,PoˆledesMaladiesduSyste`meNerveux,andCentredeRecherchede
l’InstitutduCerveauetdelaMoelleEpinie`re,UPMC/INSERMUMR_S975;CNRS
UMR7225,Paris,France
GaryA.Heiman
RutgersUniversity,DepartmentofGenetics,Piscataway,NewJersey,USA
BastianHengerer
BoehringerIngelheimPharmaGmbH&Co.KG,CNSResearch,BiberachanderRiss,
Germany
PieterJ.Hoekstra
DepartmentofPsychiatry,UniversityMedicalCenterGroningen,UniversityofGroningen,
Groningen,TheNetherlands
MasakiIsoda
DepartmentofPhysiology,KansaiMedicalUniversitySchoolofMedicine,Hirakata,Osaka,
Japan
xi
xii Contributors
GiovanniLaviola
SectionofBehaviouralNeuroscience,DepartmentCellBiologyandNeuroscience,Istituto
SuperiorediSanita`,Roma,Italy
JamesF.Leckman
ChildStudyCenter,YaleUniversity,NewHaven,Connecticut,USA
AndreaG.Ludolph
DepartmentofChildandAdolescentPsychiatry,UniversityofUlm,Ulm,Germany
AntonellaMacerollo
SobellDepartmentofMotorNeuroscienceandMovementDisorders,NationalHospitalof
NeurologyandNeurosurgery,InstituteofNeurology,UniversityCollegeLondon,London,
UnitedKingdom
SimoneMacr`ı
SectionofBehaviouralNeuroscience,DepartmentCellBiologyandNeuroscience,Istituto
SuperiorediSanita`,Roma,Italy
NamrataMadhusudan
DepartmentofNeuropsychiatry,UniversityofBirminghamandBSMHFT,Birmingham,
UnitedKingdom
MarcosMadruga-Garrido
Seccio´ndeNeuropediatr´ıa,InstitutodeBiomedicinadeSevilla,HospitalUniversitario
VirgendelRoc´ıo/UniversidaddeSevilla,Sevilla,Spain
DavideMartino
QueenElizabethHospital,Woolwich;CentreforNeuroscienceandTrauma,QueenMary
UniversityofLondon,andKing’sCollegeHospital,London,UnitedKingdom
KevinW.McCairn
SystemsNeuroscienceDivision,PrimateResearchInstitute,KyotoUniversity,Inuyama,
Aichi,Japan
PabloMir
UnidaddeTrastornosdelMovimiento,ServiciodeNeurolog´ıayNeurofisiolog´ıaCl´ınica,
InstitutodeBiomedicinadeSevilla,HospitalUniversitarioVirgendelRoc´ıo/CSIC/
UniversidaddeSevilla,andCentrodeInvestigacio´nBiome´dicaenRedsobreEnfermedades
Neurodegenerativas(CIBERNED),Sevilla,Spain
SabineMogwitz
DepartmentofChildandAdolescentPsychiatry,UniversityMedicalCenter,Technische
Univerita¨tDresden,Dresden,Germany
AndreaNani
MichaelTrimbleNeuropsychiatryResearchGroup,BSMHFTandUniversityof
Birmingham,Birmingham,UnitedKingdom
ValeriaNeri
DepartmentofPediatricsandChildNeuropsychiatry,SapienzaUniversityofRome,Rome,
Italy
Contributors xiii
EsterNespoli
DepartmentofChildandAdolescentPsychiatry,UniversityofUlm,Ulm,andBoehringer
IngelheimPharmaGmbH&Co.KG,CNSResearch,BiberachanderRiss,Germany
IreneNeuner
InstituteofNeuroscienceandMedicine4,INM4,ForschungszentrumJu¨lichGmBH,
Juelich;DepartmentofPsychiatry,PsychotherapyandPsychosomatics,RWTHAachen
University,Aachen,andJARA—TranslationalBrainMedicine,Germany
MartinaProiettiOnori
SectionofBehaviouralNeuroscience,DepartmentCellBiologyandNeuroscience,Istituto
SuperiorediSanita`,Roma,Italy
StefanoPalminteri
LaboratoiredesNeurosciencesCognitives(LNC),EcoleNormaleSupe`rieure(ENS),Paris,
France
PeristeraPaschou
DepartmentofMolecularBiologyandGenetics,DemocritusUniversityofThrace,
Alexandroupoli,Greece
MathiasPessiglione
MotivationBrainandBehaviourTeam(MBB),InstitutduCerveauetdelaMoelle(ICM),
Paris,France
FrancescaRizzo
DepartmentofChildandAdolescentPsychiatry,andInstituteofAnatomyandCellBiology,
UniversityofUlm,Ulm,Germany
RenataRizzo
DepartmentofMedicalandPediatricSciences,CataniaUniversity,Catania,Italy
VeitRoessner
DepartmentofChildandAdolescentPsychiatry,TechnicalUniversityDresden,Dresden,
Germany
GiorgioRossi
ChildNeuropsychiatryUnit,DepartmentofExperimentalMedicine,UniversityofInsubria,
Varese,Italy
FrankSchneider
DepartmentofPsychiatry,PsychotherapyandPsychosomatics,RWTHAachenUniversity,
Aachen,andJARA—TranslationalBrainMedicine,Germany
Ba`rbaraSegura
ResearchImagingCentre,CentreforAddictionandMentalHealth,UniversityofToronto,
Ontario,Canada,andDepartmentofPsychiatryandClinicalPsychobiology,Universityof
Barcelona,Barcelona,Spain
ClaudiaSelvini
ChildNeuropsychiatryUnit,DepartmentofExperimentalMedicine,UniversityofInsubria,
Varese,Italy
xiv Contributors
N.JonShah
InstituteofNeuroscienceandMedicine4,INM4,ForschungszentrumJu¨lichGmBH,
Juelich;JARA—TranslationalBrainMedicine,andDepartmentofNeurology,RWTH
AachenUniversity,Aachen,Germany
FrankSharp
DepartmentofNeurologyandMINDInstitute,UniversityofCaliforniaatDavis,
Sacramento,California,USA
AntonioP.Strafella
ResearchImagingCentre,CentreforAddictionandMentalHealth;MortonandGloria
ShulmanMovementDisorderUnit&E.J.SafraParkinsonDiseaseProgram,andDivisionof
Brain,ImagingandBehaviour—SystemsNeuroscience,TorontoWesternResearch
Institute,UHN,UniversityofToronto,Ontario,Canada
CristianoTermine
ChildNeuropsychiatryUnit,DepartmentofExperimentalMedicine,UniversityofInsubria,
Varese,Italy
PatrickT.Udvardi
DepartmentofChildandAdolescentPsychiatry,andInstituteofAnatomyandCellBiology,
UniversityofUlm,Ulm,Germany
PanagiotisZis
King’sCollegeHospital,London,UnitedKingdom
PREFACE
The Metamorphoses of Gilles de la Tourette
Syndrome
Few medical conditions have gone through as many transformation as the
“maladiedestics”sinceGeorgesGillesdelaTourette’soriginaldescription
of nine patients who presented with involuntary movements, echolalia,
echopraxia, coprolalia, and strange uncontrollable sounds (Gilles de la
Tourette, 1885). These symptoms, which were subsequently identified as
motor tics, tendencies to repeat or copy other people’s words and actions,
involuntary swearing, and vocal/phonic tics, became the hallmark features
ofafascinatingneurodevelopmentaldisorderattheinterfacebetweenneu-
rologyandpsychiatry.ItcanbearguedthatourconceptualizationofGilles
de la Tourette syndrome (often abbreviated as “Tourette syndrome” or
“TS,” especially in the Anglo-Saxon literature) went through at least four
crucial“paradigmshifts”(Kuhn,1962)throughoutitsfirst128yearsofhis-
tory (McNaught & Mink, 2011).
ThefirstconceptualshiftinvolvedGillesdelaTourettesyndrome(GTS)
core symptoms, as the chronic presence of both motor and vocal/phonic
tics, with onset in childhood or adolescence, became the key criterion for
the diagnosis of this condition since the development of modern era diag-
nostic classification schemes. Both the Diagnostic and Statistical Manual of
MentalDisorders(AmericanPsychiatricAssociation,2013)andtheInterna-
tional Classification of Diseases (World Health Organization, 1992) cur-
rently stipulate that these clinical features, when they are not caused by
underlyingbrainpathologiesoractivesubstances,arerequiredforthediag-
nosis of GTS, regardless of their severity. The very concept of tics under-
went refinement until very recently, as for instance the adjective
“stereotypic” was removed from the traditional definition of “sudden,
repetitive, nonrhythmic movements or vocalizations.” Moreover, it has
been increasingly recognized that tics represent the behavioral response to
unwanted, irresistible premonitory urges, which can be of crucial impor-
tance for the differential diagnosis between tics and other hyperkinetic
movement disorders (Cath et al., 2011), and for the success of behavioral
interventions for tic management (Frank & Cavanna, 2013). Interestingly,
complex tics such as echo- and coprophenomena, albeit pathognomonic,
are no longer considered to be essential criteria for the diagnosis of GTS.
xv
xvi Preface
Theprogressivemodificationsindiagnosticcriteriaplayedanimportantrole
inthesecondparadigmshift,asthissyndromewentfrombeingconsidereda
somewhat bizarre medical rarity to a relatively common variant of normal
human behavior, with an estimated prevalence as high as 0.3–1% in
school-age populations (Robertson, Eapen, & Cavanna, 2009; Scharf,
Miller,Mathews,&BenSchlomo,2012).Thethirdparadigmshiftreflected
the increased awareness that tics are accompanied by specific behavioral
symptoms (especially attention deficit, hyperactivity, compulsions, and
obsessions) in the vast majority of patients (Cavanna & Rickards, 2013).
ItisthereforenotsurprisingthatGTSfeaturesinbothneurologicalandpsy-
chiatric classification systems. The most significant paradigm shift was the
discoveryofthegeneticandneurobiologicalbasesofthiscondition,which
resulted in a significant change in the general attitude toward patients with
tic disorders. As a consequence, the neuroscientific paradigm gradually but
relentlesslyreplacedprevioustheoriesonthepsychologicaloriginofticsand
tic-related symptoms (Germiniani, Miranda, Ferenczy, Munhoz, & Teive,
2012).Whileitisstillacknowledgedthatbothminorlifeevents(Steinberg,
Shmuel-Baruch, Horesh, & Apter, 2013) and their emotional reactions
(Conelea & Woods,2008) can have a considerable impact on themodula-
tion of tic expression, the neurobiological bases of GTS are currently the
main focus of research efforts and inform therapeutic approaches
(Cavanna, Kavanagh, & Robertson, 2013).
This issue of International Reviews in Neurobiology is devoted to the most
recent Advances in the Neurochemistry and Neuropharmacology of Tourette Syn-
drome,inordertoprovidebothresearchersandclinicianswithacomprehen-
sive and up-to-date overview on this rapidly expanding field. The present
volume opens with two introductory chapters. In the first, we give a
necessary overview on the clinical phenomenology of GTS, including
recent studies using statistical techniques such as factor analysis and hierar-
chical cluster analysis to identify the multiplephenotypes of thesyndrome.
This is followed by a comprehensive review by Neuner et al. on the brain
structural and functional alterations that have been associated with GTS.
After these two introductory chapters, the volume offers a detailed
overview of the pathobiology of neurotransmitter systems in this
condition. A large body of evidence dissected the complex neurochemistry
ofGTS,depictingitasa“network”disorderinvolvingdifferentneurotrans-
mitters along the course of brain maturation. It is not surprising that the
complexity of the neurochemical basis of GTS parallels that of its phenom-
enological conundrum presented in the first chapter. The involvement of
Preface xvii
cortico-striato-thalamo-cortical circuits, with concurrent abnormalities of
dopaminergic, serotoninergic, noradrenergic, glutamatergic, and gamma-
aminobutyric acid (GABA)-ergic systems, is now undisputed. As for the
majority of neuropsychiatric disorders, functional imaging, and mainly
nuclear medicine techniques employing radioligands for proteins associated
withneurotransmitter systems, allowedthenoninvasiveexploration ofthese
neurotransmittersalsoinGTS.SeguraandStrafellareviewedtheevidenceof
functionalimaging researchon dopaminergic transmission in this condition,
showing how the dysfunction of dopaminergic transmission may extend
beyond the segregated cortico-striato-thalamo-cortical loops, in line with
the breadth of the behavioral and cognitive spectrum exhibited by these
patients. In her chapter, Ludolph confirms the multiple neurotransmitter
“nature” of TS and summarizes the available functional imaging evidence
in support of this.
Thehighrelevanceofdopaminergicdysfunctiontothecorepathophys-
iology of tics and related behavioral anomalies has been recently explored
through a cognitive approach, based on the analysis of decision-making
and reinforcement learning processes. Often this approach has utilized the
samedopaminereceptor-modulatingagentsusedtocontrolticsintheclinic.
PalminteriandPessiglioneelaborateonthisnovelareaofcognitiveresearch
inthestudyofGTS,whichhasveryimportantimplicationsfor bothphar-
macological and cognitive–behavioral management of tics.
Despite the high frequency of familial occurrence of GTS, the classical,
“past generation,” genetic linkage approach has not been rewarding. The
complexity of the clinical phenotype is certainly, at least in part, responsible
forthis.Moreover,next-generationDNAsequencingtechniquesandtherev-
olutionary role of epigenetics are likely to provide crucial advances in the
understanding of the multifactorial genetic susceptibility to this condition,
andprobablyevenguideareappraisalofitsnosography.Paschouetal.summa-
rizegeneticandgeneexpressionfindingsoncandidateneurotransmittergenes
and comment on a breakthrough large pedigree analysis that introducedthe
potentialroleofhistamineinthepathophysiologicalinterplayofticdisorders.
Oneofthemainproblemsfacedbyresearchersinthisfieldhastradition-
ally been the difficulty in developing informative animal models for tics.
Theseissuesareofgreat relevancefor theunderstandingofthepathophys-
iologyandthedevelopmentofnewtreatmentsforpatientswithGTS.The
chaptersbyMcCairnandIsoda,focusingonthepharmacologicalapproach,
and by Macr`ı et al., focusing on genetic and immunological approaches to
animal models of tic disorders, cover these topics in great depth.
xviii Preface
An underinvestigated area in the neurobiology of GTS is the cross talk
betweennervousandendocrinesystems.Thereispreliminary,butinfluen-
tial,evidenceofaroleplayedbygonadalandstresshormonesinthenatural
history of this condition, and the chapter by Martino, Macerollo, and
Leckman aims at filling this literature gap.
Thefinalpartofthevolumedelineatesthecontinuouslychangingrela-
tionshipbetweenpharmacologicalagentsandthemanagementofticdisor-
ders and related comorbidities. Pharmacological treatment of GTS is
enteringanewera.Theincreasedawarenessoftheroleofpsychoeducation
and social support, the refinement of cognitive–behavioral treatment
approaches, and the highly promising results of deep brain stimulation for
themanagementofotherwise“refractory”patientswiththisconditionforce
clinicianstobothselectmorecarefullypatientswhorequirepharmacological
treatment and tailor drug choice on the individual patient. Dopamine
receptor-modulating agents have dominated the scene of pharmacological
treatment for decades. The growing experience of clinicians in managing
GTS with these drugs has differentiated the approach to antipsychotic
use in tic disorders from the one in psychosis. Specific dopamine
receptor-modulating agents, first among all aripiprazole, are showing their
value, and new compounds acting on the same neurotransmitter system
arecurrentlybeinginvestigated.Mogwitzetal.giveadetailedandsystem-
aticoverviewonthisclassofdrugsandtheiruseinGTS.Inhisdetailedchap-
ter, Hartmann offers a useful round up of all the available evidence on
compounds active on other neurotransmitter systems. This topic is once
more very important in view of a tailored approach to drug management
of tic disorders: one example above all is the demonstration, through
meta-analysis of existing trials, that a agonists such as clonidine and gua-
2
nfacine, previously considered indiscriminately as first-line agents in the
treatmentoftics,aretrulyeffectiveonlyonpatientswithGTSandcomorbid
attention deficit hyperactivitydisorder (ADHD).Cavanna andNani tackle
theneglectedissueofticmanagementwithantiepilepticdrugs.Thisareahas
attracted interest following the publication of a handful of trials, some of
which promising,and probablydeserves moreinterest,given themultifac-
eted pharmacodynamics of many antiepileptic agents.
The treatment of the two most common comorbidities of GTS,
obsessive–compulsivedisorder(OCD)andADHD,isanareaofgreatinter-
esttotheclinician,giventheimpactonqualityoflifeandfunctionaldisabil-
ity of these two conditions and the current trend for individually tailored
interventions. In spite of this, good-quality clinical trials on ADHD