PREFACE The Metamorphoses of Gilles de la Tourette Syndrome Few medical conditions have gone through as many transformation as the “maladie des tics” since Georges Gilles de la Tourette’s original description 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 of a fascinating neurodevelopmental disorder at the interface between neurology and psychiatry. It can be argued that our conceptualization of Gilles de la Tourette syndrome (often abbreviated as “Tourette syndrome” or “TS,” especially in the Anglo-Saxon literature) went through at least four crucial “paradigm shifts” (Kuhn, 1962) throughout its first 128 years of history (McNaught & Mink, 2011). The first conceptual shift involved Gilles de la Tourette syndrome (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 diagnostic classification schemes. Both the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 2013) and the International Classification of Diseases (World Health Organization, 1992) currently stipulate that these clinical features, when they are not caused by underlying brain pathologies or active substances, are required for the diagnosis of GTS, regardless of their severity. The very concept of tics underwent 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 importance 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
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The progressive modifications in diagnostic criteria played an important role in the second paradigm shift, as this syndrome went from being considered a 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, & Ben Schlomo, 2012). The third paradigm shift reflected 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). It is therefore not surprising that GTS features in both neurological and psychiatric classification systems. The most significant paradigm shift was the discovery of the genetic and neurobiological bases of this condition, which resulted in a significant change in the general attitude toward patients with tic disorders. As a consequence, the neuroscientific paradigm gradually but relentlessly replaced previous theories on the psychological origin of tics and tic-related symptoms (Germiniani, Miranda, Ferenczy, Munhoz, & Teive, 2012). While it is still acknowledged that both minor life events (Steinberg, Shmuel-Baruch, Horesh, & Apter, 2013) and their emotional reactions (Conelea & Woods, 2008) can have a considerable impact on the modulation 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 Syndrome, in order to provide both researchers and clinicians with a comprehensive 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 hierarchical cluster analysis to identify the multiple phenotypes of the syndrome. 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 of GTS, depicting it as a “network” disorder involving different neurotransmitters along the course of brain maturation. It is not surprising that the complexity of the neurochemical basis of GTS parallels that of its phenomenological conundrum presented in the first chapter. The involvement of
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cortico-striato-thalamo-cortical circuits, with concurrent abnormalities of dopaminergic, serotoninergic, noradrenergic, glutamatergic, and gammaaminobutyric 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 with neurotransmitter systems, allowed the noninvasive exploration of these neurotransmitters also in GTS. Segura and Strafella reviewed the evidence of functional imaging research on 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. The high relevance of dopaminergic dysfunction to the core pathophysiology 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 same dopamine receptor-modulating agents used to control tics in the clinic. Palminteri and Pessiglione elaborate on this novel area of cognitive research in the study of GTS, which has very important implications for both pharmacological 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 for this. Moreover, next-generation DNA sequencing techniques and the revolutionary role of epigenetics are likely to provide crucial advances in the understanding of the multifactorial genetic susceptibility to this condition, and probably even guide a reappraisal of its nosography. Paschou et al. summarize genetic and gene expression findings on candidate neurotransmitter genes and comment on a breakthrough large pedigree analysis that introduced the potential role of histamine in the pathophysiological interplay of tic disorders. One of the main problems faced by researchers in this field has traditionally been the difficulty in developing informative animal models for tics. These issues are of great relevance for the understanding of the pathophysiology and the development of new treatments for patients with GTS. The chapters by McCairn and Isoda, focusing on the pharmacological approach, and by Macrı` et al., focusing on genetic and immunological approaches to animal models of tic disorders, cover these topics in great depth.
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An underinvestigated area in the neurobiology of GTS is the cross talk between nervous and endocrine systems. There is preliminary, but influential, evidence of a role played by gonadal and stress hormones in the natural history of this condition, and the chapter by Martino, Macerollo, and Leckman aims at filling this literature gap. The final part of the volume delineates the continuously changing relationship between pharmacological agents and the management of tic disorders and related comorbidities. Pharmacological treatment of GTS is entering a new era. The increased awareness of the role of psychoeducation and social support, the refinement of cognitive–behavioral treatment approaches, and the highly promising results of deep brain stimulation for the management of otherwise “refractory” patients with this condition force clinicians to both select more carefully patients who require pharmacological 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 are currently being investigated. Mogwitz et al. give a detailed and systematic overview on this class of drugs and their use in GTS. In his detailed chapter, 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 a2 agonists such as clonidine and guanfacine, previously considered indiscriminately as first-line agents in the treatment of tics, are truly effective only on patients with GTS and comorbid attention deficit hyperactivity disorder (ADHD). Cavanna and Nani tackle the neglected issue of tic management with antiepileptic drugs. This area has attracted interest following the publication of a handful of trials, some of which promising, and probably deserves more interest, given the multifaceted pharmacodynamics of many antiepileptic agents. The treatment of the two most common comorbidities of GTS, obsessive–compulsive disorder (OCD) and ADHD, is an area of great interest to the clinician, given the impact on quality of life and functional disability of these two conditions and the current trend for individually tailored interventions. In spite of this, good-quality clinical trials on ADHD
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treatment in GTS are numerically limited, whereas clinical trials on OCD treatment in GTS are lacking. Clinical decisions mainly rely on available evidence on the treatment of these comorbidities when occurring in the absence of a concurrent tic disorder. The chapters from Neri and Cardona and Rizzo and Gulisano give us a picture of the current state of the art, clearly pointing out that new, good-quality clinical trials would not only aid management decisions but also give useful insight on the neurobiology underlying comorbidity. The conclusive chapters of the volume cover aspects that are often neglected in the literature. Termine et al. display the current research scenario, guiding the reader through what is in the pipeline in the management of tics. Madruga-Garrido and Mir end this volume with an overview of iatrogenic tic disorders and their clinical and pathophysiological relationship with other, much more common, drug-induced movement disorders. Knowledge of the neurobiology of GTS and related disorders is increasing. Likely, this will translate into better use of already existing therapeutic interventions and development of new, more effective, and better tolerated ones. The evidence supporting the use of nonpharmacological interventions to control tics and other related behavioral anomalies is also increasing. The spin-off to this new perspective in the management of GTS is likely to be a more thoughtful use of medications. We believe this will lead, in the near future, to a closer and more focused cross talk between neurobiological and clinical research in this fascinating “network,” neurodevelopmental disorder. Davide Martino Andrea E. Cavanna
REFERENCES American Psychiatric Association (2013). Diagnostic and statistical manual for mental disorders (DSM-5) (5th ed.). Washington, DC: Author. Cath, D. C., Hedderly, T., Ludolph, A. G., Stern, J. S., Murphy, T., Hartmann, A., et al. (2011). European clinical guidelines for Tourette syndrome and other tic disorders. Part I: Assessment. European Child & Adolescent Psychiatry, 20, 155–171. Cavanna, A. E., Kavanagh, C., & Robertson, M. M. (2013). The future of research in Tourette syndrome. Behavioural Neurology, 27, 139–142. Cavanna, A. E., & Rickards, H. (2013). The psychopathological spectrum of Gilles de la Tourette syndrome. Neuroscience and Biobehavioral Reviews, 37, 1008–1015. Conelea, C. A., & Woods, D. W. (2008). The influence of contextual factors on tic expression in Tourette’s syndrome: A review. Journal of Psychosomatic Research, 65, 487–496. Frank, M., & Cavanna, A. E. (2013). Behavioural treatments for Tourette syndrome: An evidence-based review. Behavioural Neurology, 27, 105–117.
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Germiniani, F. M., Miranda, A. P., Ferenczy, P., Munhoz, R. P., & Teive, H. A. (2012). Tourette’s syndrome: From demonic possession and psychoanalysis to the discovery of gene. Arquivos de Neuropsiquiatria, 70, 547–549. Gilles de la Tourette, G. (1885). Etude sur une affection nerveuse caracterise´e par de l’incoordination motrice accompagne´e d’e´cholalie et de copralalie. Archives de Neurologie, 9(19–42), 158–200. Kuhn, T. S. (1962). The structure of scientific revolutions. Chicago, IL: University of Chicago Press. Kushner, H. I. (1999). A cursing brain? The histories of Tourette syndrome. Cambridge: Harvard University Press. McNaught, K. S., & Mink, J. W. (2011). Advances in understanding and treatment of Tourette syndrome. Nature Reviews Neurology, 7, 667–676. Robertson, M. M., Eapen, V., & Cavanna, A. E. (2009). The international prevalence, epidemiology and clinical phenomenology of Tourette syndrome: A cross-cultural perspective. Journal of Psychosomatic Research, 67, 475–483. Scharf, J. M., Miller, L. L., Mathews, C. A., & Ben Schlomo, Y. (2012). Prevalence of Tourette syndrome and chronic tics in the population-based Avon longitudinal study of parents and children cohort. Journal of the American Academy of Child and Adolescent Psychiatry, 51, 192–201. Steinberg, T., Shmuel-Baruch, S., Horesh, N., & Apter, A. (2013). Life events and Tourette syndrome. Comprehensive Psychiatry, 54, 467–473. World Health Organization (1992). International statistical classification of diseases and related health problems: ICD-10 (10th revision). Geneva: Author.
xvi
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The progressive modifications in diagnostic criteria played an important role in the second paradigm shift, as this syndrome went from being considered a 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, & Ben Schlomo, 2012). The third paradigm shift reflected 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). It is therefore not surprising that GTS features in both neurological and psychiatric classification systems. The most significant paradigm shift was the discovery of the genetic and neurobiological bases of this condition, which resulted in a significant change in the general attitude toward patients with tic disorders. As a consequence, the neuroscientific paradigm gradually but relentlessly replaced previous theories on the psychological origin of tics and tic-related symptoms (Germiniani, Miranda, Ferenczy, Munhoz, & Teive, 2012). While it is still acknowledged that both minor life events (Steinberg, Shmuel-Baruch, Horesh, & Apter, 2013) and their emotional reactions (Conelea & Woods, 2008) can have a considerable impact on the modulation 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 Syndrome, in order to provide both researchers and clinicians with a comprehensive 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 hierarchical cluster analysis to identify the multiple phenotypes of the syndrome. 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 of GTS, depicting it as a “network” disorder involving different neurotransmitters along the course of brain maturation. It is not surprising that the complexity of the neurochemical basis of GTS parallels that of its phenomenological 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 gammaaminobutyric 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 with neurotransmitter systems, allowed the noninvasive exploration of these neurotransmitters also in GTS. Segura and Strafella reviewed the evidence of functional imaging research on 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. The high relevance of dopaminergic dysfunction to the core pathophysiology 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 same dopamine receptor-modulating agents used to control tics in the clinic. Palminteri and Pessiglione elaborate on this novel area of cognitive research in the study of GTS, which has very important implications for both pharmacological 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 for this. Moreover, next-generation DNA sequencing techniques and the revolutionary role of epigenetics are likely to provide crucial advances in the understanding of the multifactorial genetic susceptibility to this condition, and probably even guide a reappraisal of its nosography. Paschou et al. summarize genetic and gene expression findings on candidate neurotransmitter genes and comment on a breakthrough large pedigree analysis that introduced the potential role of histamine in the pathophysiological interplay of tic disorders. One of the main problems faced by researchers in this field has traditionally been the difficulty in developing informative animal models for tics. These issues are of great relevance for the understanding of the pathophysiology and the development of new treatments for patients with GTS. The chapters by McCairn and Isoda, focusing on the pharmacological approach, and by Macrı` 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 between nervous and endocrine systems. There is preliminary, but influential, evidence of a role played by gonadal and stress hormones in the natural history of this condition, and the chapter by Martino, Macerollo, and Leckman aims at filling this literature gap. The final part of the volume delineates the continuously changing relationship between pharmacological agents and the management of tic disorders and related comorbidities. Pharmacological treatment of GTS is entering a new era. The increased awareness of the role of psychoeducation and social support, the refinement of cognitive–behavioral treatment approaches, and the highly promising results of deep brain stimulation for the management of otherwise “refractory” patients with this condition force clinicians to both select more carefully patients who require pharmacological 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 are currently being investigated. Mogwitz et al. give a detailed and systematic overview on this class of drugs and their use in GTS. In his detailed chapter, 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 a2 agonists such as clonidine and guanfacine, previously considered indiscriminately as first-line agents in the treatment of tics, are truly effective only on patients with GTS and comorbid attention deficit hyperactivity disorder (ADHD). Cavanna and Nani tackle the neglected issue of tic management with antiepileptic drugs. This area has attracted interest following the publication of a handful of trials, some of which promising, and probably deserves more interest, given the multifaceted pharmacodynamics of many antiepileptic agents. The treatment of the two most common comorbidities of GTS, obsessive–compulsive disorder (OCD) and ADHD, is an area of great interest to the clinician, given the impact on quality of life and functional disability of these two conditions and the current trend for individually tailored interventions. In spite of this, good-quality clinical trials on ADHD
Preface
xix
treatment in GTS are numerically limited, whereas clinical trials on OCD treatment in GTS are lacking. Clinical decisions mainly rely on available evidence on the treatment of these comorbidities when occurring in the absence of a concurrent tic disorder. The chapters from Neri and Cardona and Rizzo and Gulisano give us a picture of the current state of the art, clearly pointing out that new, good-quality clinical trials would not only aid management decisions but also give useful insight on the neurobiology underlying comorbidity. The conclusive chapters of the volume cover aspects that are often neglected in the literature. Termine et al. display the current research scenario, guiding the reader through what is in the pipeline in the management of tics. Madruga-Garrido and Mir end this volume with an overview of iatrogenic tic disorders and their clinical and pathophysiological relationship with other, much more common, drug-induced movement disorders. Knowledge of the neurobiology of GTS and related disorders is increasing. Likely, this will translate into better use of already existing therapeutic interventions and development of new, more effective, and better tolerated ones. The evidence supporting the use of nonpharmacological interventions to control tics and other related behavioral anomalies is also increasing. The spin-off to this new perspective in the management of GTS is likely to be a more thoughtful use of medications. We believe this will lead, in the near future, to a closer and more focused cross talk between neurobiological and clinical research in this fascinating “network,” neurodevelopmental disorder. Davide Martino Andrea E. Cavanna
REFERENCES American Psychiatric Association (2013). Diagnostic and statistical manual for mental disorders (DSM-5) (5th ed.). Washington, DC: Author. Cath, D. C., Hedderly, T., Ludolph, A. G., Stern, J. S., Murphy, T., Hartmann, A., et al. (2011). European clinical guidelines for Tourette syndrome and other tic disorders. Part I: Assessment. European Child & Adolescent Psychiatry, 20, 155–171. Cavanna, A. E., Kavanagh, C., & Robertson, M. M. (2013). The future of research in Tourette syndrome. Behavioural Neurology, 27, 139–142. Cavanna, A. E., & Rickards, H. (2013). The psychopathological spectrum of Gilles de la Tourette syndrome. Neuroscience and Biobehavioral Reviews, 37, 1008–1015. Conelea, C. A., & Woods, D. W. (2008). The influence of contextual factors on tic expression in Tourette’s syndrome: A review. Journal of Psychosomatic Research, 65, 487–496. Frank, M., & Cavanna, A. E. (2013). Behavioural treatments for Tourette syndrome: An evidence-based review. Behavioural Neurology, 27, 105–117.
xx
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Germiniani, F. M., Miranda, A. P., Ferenczy, P., Munhoz, R. P., & Teive, H. A. (2012). Tourette’s syndrome: From demonic possession and psychoanalysis to the discovery of gene. Arquivos de Neuropsiquiatria, 70, 547–549. Gilles de la Tourette, G. (1885). Etude sur une affection nerveuse caracterise´e par de l’incoordination motrice accompagne´e d’e´cholalie et de copralalie. Archives de Neurologie, 9(19–42), 158–200. Kuhn, T. S. (1962). The structure of scientific revolutions. Chicago, IL: University of Chicago Press. Kushner, H. I. (1999). A cursing brain? The histories of Tourette syndrome. Cambridge: Harvard University Press. McNaught, K. S., & Mink, J. W. (2011). Advances in understanding and treatment of Tourette syndrome. Nature Reviews Neurology, 7, 667–676. Robertson, M. M., Eapen, V., & Cavanna, A. E. (2009). The international prevalence, epidemiology and clinical phenomenology of Tourette syndrome: A cross-cultural perspective. Journal of Psychosomatic Research, 67, 475–483. Scharf, J. M., Miller, L. L., Mathews, C. A., & Ben Schlomo, Y. (2012). Prevalence of Tourette syndrome and chronic tics in the population-based Avon longitudinal study of parents and children cohort. Journal of the American Academy of Child and Adolescent Psychiatry, 51, 192–201. Steinberg, T., Shmuel-Baruch, S., Horesh, N., & Apter, A. (2013). Life events and Tourette syndrome. Comprehensive Psychiatry, 54, 467–473. World Health Organization (1992). International statistical classification of diseases and related health problems: ICD-10 (10th revision). Geneva: Author.
