Neuropsychological Triggering Factors in Musicians with ...

University of Veterinary Medicine Hannover

Institute of Music Physiology and Musicians’ Medicine Hannover University of Music, Drama and Media

Centre for Systems Neuroscience (ZSN)

Neuropsychological Triggering Factors in Musicians

with Focal Dystonia

THESIS

Submitted in partial fulfilment of the requirements for the degree

DOCTOR OF PHILOSOPHY

(PhD)

awarded by the University of Veterinary Medicine Hannover

by

Christos I. Ioannou

Born in Paphos, Cyprus

Hannover, Germany, 2015

Supervisor: Prof. Dr. med. Eckart Altenmüller, MD, MA Supervision Group: Prof. Dr. med. Reinhard Dengler, MD

Prof. Dr. rer. nat. Claudia Grothe 1st Evaluation: Prof. Dr. med. Eckart Altenmüller, MD, MA

Institute of Music Physiology and Musicians’ Medicine Hannover University of Music, Drama and Media Prof. Dr. med. Reinhard Dengler, MD Department of Neurology Hannover Medical School Prof. Dr. rer. nat. Claudia Grothe Institute of Neuroanatomy Hannover Medical Schoolon:

2nd Evaluation: Prof. Dr. med. Harald Gündel

Department of Psychosomatic Medicine and Psychotherapy University of Ulm

Date of final exam: 06.11.2015

Parts of the thesis have been published previously in:

Ioannou, C. I., & Altenmüller, E. (2014). Psychological characteristics in musician's dysto-nia: a new diagnostic classification. Neuropsychologia, 61, 80-88.

Ioannou, C. I., Furuya, S., & Altenmüller, E. (in press). Objective evaluation of perfor-mance stress in musicians with focal dystonia: a case study. Journal of Motor Behavior.

Ioannou, C. I., Furuya, S., & Altenmüller, E. (2016). The impact of stress on motor performance in skilled musicians suffering from focal dystonia: physiological and psy-chological characteristics. Neuropsychologia, 58, 226-236.

Sponsorship: The whole project was funded by the German Research Foundation (DFG), (AL269/8-1).

To my dear parents Xenia and Yiannis for their support, encouragement and unconditional love…

Thank you!

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Table of Contents

INTRODUCTION .................................................................................................................... 5

1 Dystonia ........................................................................................................................................ 7 1.1 Historical overview ............................................................................................................................ 7 1.2 Clinical characteristics ....................................................................................................................... 7 1.3 Classification ..................................................................................................................................... 8 1.4 Epidemiology and pathophysiology .................................................................................................. 9

2 Focal dystonia in musicians ........................................................................................................ 10 2.1 Clinical features and classification .................................................................................................. 10 2.2 Epidemiology and aetiology ............................................................................................................ 11 2.3 Genetics and heredity ...................................................................................................................... 12 2.4 Pathophysiology .............................................................................................................................. 12

2.4.1 Structural and functional abnormalities ............................................................................... 12 2.4.2 Dysfunction of the Basal Ganglia ........................................................................................ 14 2.4.3 Loss of inhibition ................................................................................................................. 15 2.4.4 Maladaptive plasticity and sensory dysfunction .................................................................. 16

2.5 Treatment methods .......................................................................................................................... 17

3 Psycho-psychiatric features ......................................................................................................... 19 3.1 Psychopathology in primary focal dystonia .................................................................................... 19 3.2 Psychopathology in Musician’s Dystonia ....................................................................................... 21

4 Aims ............................................................................................................................................ 24

CHAPTERS ............................................................................................................................ 25

Psychological Characteristics in Musician's Dystonia: A New Diagnostic Classification .......... 27

Objective Evaluation of Performance Stress in Musicians with Focal Dystonia: A Case series ...................................................................................................................................... 29

The Impact of Stress on Motor Performance in Skilled Musicians Suffering from Focal Dystonia: Physiological and Psychological Characteristics ........................................................... 31

CONCLUSIONS AND OUTLOOK ..................................................................................... 33

Conclusions .................................................................................................................................... 35 Future aspects ................................................................................................................................. 37 Definition ....................................................................................................................................... 37

REFERENCES ....................................................................................................................... 39

AFFIDAVIT ........................................................................................................................... 53

ACKNOWLEDGEMENTS .................................................................................................. 55

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List of abbreviations

A AA active avoidance subscale of the SCQ ARI adjusted rand index

B BL1 1st baseline

BL2 2nd baseline BLA basolateral amygdala BMI body mass index bpm beats per minute BTX botulinum toxin

C CI co-activation index

CM concern over mistakes subscale of the FMPS CNS central nervous system CTAI Competitive Trait Anxiety Inventory CTAIcp concentration problems subscale of the CTAI CTAIsa somatic anxiety subscale of the CTAI CTAIsdc self-doubt concern subscale of the CTAI CV coefficient of variance

D D distraction subscale of the SCQ DA doubts about actions subscale of the FMPS DSM-IV Diagnostic and Statistical Manual of Mental disorders, 4th

edition E ECG electrocardiography

ECLIA electrochemiluminescence immunoassay ED embouchure dystonia EMG electromyography

F FDM focal dystonia in musicians

FH– no family history FH+ positive family history FHD focal hand dystonia FMPS Frost Multidimensional Perfectionism Scale fMRI functional magnetic resonance imaging FPI-R Freiburg Personality Inventory FT flight tendency subscale of the SCQ

G GABA γ-Aminobutyric acid

GD guilt denial subscale of the SCQ GPe external globus pallidus GPi internal globus pallidus GZ grey zone

H HM healthy musicians

HPA axis hypothalamic-pituitary-adrenal axis HPE high psychological effects subgroup IMMM Institute of Music Physiology and Musicians’ Medicine

I IOI inter-onset interval

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L LPE low psychological effects subgroup

M max maximum MEG magneto-encephalography

min minimum MP mental perseveration subscale of the SCQ MRI magnetic resonance imaging MRS magnetic resonance spectroscopy MVC maximum voluntary contraction

N NEO-FFI NEO Five-Factor Inventory

nmol/L nanomoles per litre NSC need for social support subscale of the SCQ O organisation subscale of the FMPS OCD obsessive compulsive symptoms

P PC parental criticism subscale of the FMPS

PD play down subscale of the SCQ PE parental expectations subscale of the FMPS PET positron emission tomography PM premotor cortex PS personal standards subscale of the FMPS PSI positive self-instruction subscale of the SCQ PT post treatment

Q Q quartile

QCC Competence and Control Orientation inventory

R R resignation subscale of the SCQ RC reaction control subscale of the SCQ RI Rand index RP recovery period

S s-STAI state anxiety scale of the STAI

S1 somatosensory cortex SC situation control subscale of the SCQ SCQ Stress Coping Questionnaire SCQ-NEG negative stress coping subscales of the SCQ SCQ-POS positive stress coping subscales of the SCQ SI self-incrimination subscale of the SCQ SMA supplementary motor area SNc substantia nigra pars compacta SS substitutional satisfaction subscale of the SCQ STAI State-Trait Anxiety Inventory STN subthalamic nucleus Stress-NR stress non-responders Stress-R stress-responders

T TDCS transcranial direct-current stimulation

TMS transcranial magnetic stimulation TSST Trier Social Stress Test

W WP1 1st waiting period

WP2 2nd waiting period WU warm-up

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List of figures and tables

Introduction Fig. 1 Typical dystonic postures in musicians .................................................................................. 11 Fig. 2 Triggering factors contributing to the manifestation of FDM ................................................ 17 Fig. 3 Emotionally-induced memory consolidation in FDM patients with psychopathology .......... 23

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Summary

Neuropsychological Triggering Factors in Musicians with Focal Dystonia

Christos I. Ioannou

Focal dystonia is a neurological movement disorder which affects the fine motor control of a specific body location. In professional musicians, a limb or the embouchure involved in playing a musical instrument may be impacted. Focal dystonia in musicians (FDM) is characterised by a loss of voluntary motor control and can be a career-ending condition. The pathophysiology of focal dystonia, which remains incompletely understood, is mainly associated with dysfunction of basal ganglia-thalamo-cortical circuits, with impaired inhibition and dysfunctions of sensorimotor pathways. FDM is triggered by various neuropsychological and environmental factors. However the existence of psycho-psychiatric comorbidities and their possible impact on and/or contribution to the manifestation of FDM remains under-investigated. Recent studies have revealed that motor function can be altered as a result of psychological or psychiatric conditions, suggesting common neurobiological networks. Studies conducted in other forms of focal dystonia have uncovered psychiatric or other psychological comorbidities such as obsessions, phobias, anxieties and depression, whereas a limited number of investigations with FDM patients have mainly indicated elevated levels of anxiety and perfectionism. The aim of the current thesis was to provide new insights into the psychopathology of focal dystonia and its possible consequences for motor performance in affected musicians. The investigation was divided into three different studies (chapters), each exploring a different aspect of the overall topic.

The first chapter comprises a comprehensive exploratory analysis of the psychological profile of FDM patients based on standardised psycho-diagnostic instruments. Findings indicate that in comparison to healthy controls, half of the FDM patients exhibited elevated instances of psychological traits related to anxiety, perfectionism and dysfunctional stress-coping features. Furthermore, results suggest that these conditions pre-dated the onset of the disease and may have contributed as aggravating risk factors to the development of FDM. We suggest that the existence of FDM patients with and without psychopathology could reflect different mal-adaptive processes mediated via different circuits of the cortico-basal ganglia-thalamic loops.

Most of the features in the FDM patients diagnosed with psychopathology were related to elevated levels of stress and anxiety. Therefore the second chapter focuses on the design of a complex experimental paradigm which examines physiological parameters (electro-myography [EMG] and fine motor performance) in relaxed and stressful conditions, in combination with objective assessments (electrocardiography [ECG], cortisol) of the hypothalamic-pituitary-adrenal (HPA) axis. Due to the fact that no similar paradigm has previously been implemented for patients with focal dystonia, a pilot study with a small number of patients was conducted. Findings suggest that the experimental design is feasible and serves its purpose.

The final chapter encompasses a combined design derived from the first two chapters. Possible electrophysiological differences were examined i) between FDM patients and healthy controls, ii) among FDM patients before and after stress and iii) between patients with and without psychopathology. Findings indicate that FDM patients are characterised by increased sensitivity to psychosocial stressors, in comparison to healthy controls. The impact of stress is expressed as an increase in muscular co-contraction of the affected hand, which can be explained as a “natural” physiological response under stressful conditions. Finally, no

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motor outcome differences are found between patients with and without psychopathology, however results indicate that musicians with psychopathology had, on average, developed dystonia around a decade earlier than the remainder of the patients, emphasising the contribution of psycho-psychiatric conditions to the manifestation of dystonia.

Summarising, the current thesis suggests the existence of psychopathology in about 50% of musicians with focal dystonia. FDM patients with and without psychopathology did not differ in their motor performance, however there is clear evidence that psychopathology can be an aggravating factor, which may accelerate or even trigger the manifestation of dystonia. The current thesis supports the concept that motor and psycho-psychiatric features share common neurobiological networks in patients with focal dystonia.

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Zusammenfassung

Psychologische Faktoren als Auslöser der Musikerdystonie

Christos I. Ioannou

Die fokale Dystonie ist eine neurologische Krankheit, die sich in unwillkürlichen Verkrampfungen, Fehlbewegungen und Verlust der feinmotorischen Kontrolle eines umschriebenen Körperteils auswirkt. Bei Berufsmusikern tritt diese Erkrankung meist aufgabenspezifisch als Handdystonie oder als Ansatzdystonie beim Spiel des Instrumentes auf. Nicht selten bedroht die fokale Musikerdystonie (FDM) die Berufsfähigkeit. Die Pathophysiologie der Erkrankung ist noch nicht völlig aufgeklärt. Einerseits werden Dysfunktionen der Basalganglienschleife vermutet, andererseits ein Inhibitionsdefizit in sensomotorischen Netzwerken und/oder maladaptive Plastizität auf allen Ebenen der motorischen Systeme. Obwohl schon länger bekannt ist, dass verschiedene psychologische Faktoren zur Auslösung der Musikerdystonie beitragen können, sind diese psychischen Komorbiditäten bislang nicht ausreichend erforscht worden. Bereits seit längerem wird angenommen, dass motorische Funktionen durch psychologische Faktoren und psychiatrische Erkrankungen beeinflusst werden können, was für eine gemeinsame neurobiologisch-strukturelle Verankerung spricht. So konnten in Studien zu anderen Dystonien psychiatrische Begleiterkrankungen wie Zwangskrankheiten, Phobien, Angststörungen und Depressionen überdurchschnittlich häufig nachgewiesen werden. Untersuchungen zur Musikerdystonie ergaben vor allem Hinweise auf erhöhte Angstbereitschaft und auf perfektionistische Charakterstrukturen. Das Ziel dieser These war, neue Einsichten hinsichtlich psychopathologischer Auslöser und Begleiterscheinungen der Musikerdystonie zu gewinnen und mögliche Auswirkungen dieser Komorbiditäten auf die Spielfertigkeit zu untersuchen. Die Untersuchung dieser Fragen ist in drei verschiedenen Studien in jeweils separierten Kapiteln dargestellt.

Das erste Kapitel widmet sich einer umfassenden explorativen Analyse der psychologischen Profile gesunder Musiker und Musiker mit Musikerdystonie auf der Grundlage standardisierter psychodiagnostischer Instrumente. Die Ergebnisse zeigen, dass im Vergleich zu gesunden Musikern die Hälfte der Dystoniepatienten erhöhte Angstbereitschaft, Perfektionismus und dysfunktionale Stress-Coping-Mechanismen aufwiesen. Darüberhinaus deuten die Ergebnisse darauf hin, dass diese psychologischen Charakteristika bereits vor Ausbruch der Dystonie nachweisbar waren und möglicherweise als Risikofaktoren zur Auslösung der Dystonie beitrugen. Die Existenz von zwei unterschiedlichen Kategorien von Musikerdystonien mit oder ohne psychopathologische Komorbiditäten könnte auf unterschiedlichen maladaptiven Prozessen in spezifischen Segmenten der Basal-ganglienschleife beruhen.

Da die vorherrschenden psychopathologischen Befunde mit erhöhter Stress- und Angstbereitschaft einhergingen, konzentrierte sich die zweite Studie auf ein experimentelles Design, das unter experimentellen Bedingungen Stressreagibilität, motorische Leistung und psychophysiologische Parameter (Elektromyographie, Elektrokardiographie, Cortisolspiegel im Speichel) objektiv unter Ruhebedingungen und unter Stress erfasste. Da bislang kein derartiges experimentelles Paradigma bei Musikern mit Dystonie existierte, wurde zunächst an wenigen Probanden eine Pilotstudie durchgeführt. Die Ergebnisse dieser Studie zeigten, dass das Experiment in der geplanten Art und Weise durchführbar war.

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Das dritte Kapitel umfasst eine große Untersuchung, in der die experimentellen Designs beider Studien kombiniert wurden. Unterschiede in psychophysiologischen Parametern und in der motorischen Leistung wurden a.) zwischen gesunden Musikern und Musikern mit Dystonien und b.) bei Musikern mit Dystonie vor und nach Stress, und c.) bei Musikern mit Dystonie und unterschiedlichen psychopathologischen Profilen erfasst. Die Studie ergab, dass Musiker mit Dystonie im Vergleich zu gesunden Musikern eine deutlich erhöhte Stressbereitschaft haben. Stress wirkte sich bei gesunden und bei erkrankten Musikern vor allem in einer muskulären Kokontraktion bei feinmotorischen Leistungen, etwa dem Tonleiterspiel, aus. Dies kann als eine physiologische Reaktion auf psychische Anspannung aufgefasst werden. Das Tonleiterspiel unterschied sich nicht bei Patienten mit oder ohne psychischen Komorbiditäten. Ein interessantes Nebenergebnis war, dass Musiker mit psychopathologischen Komorbiditäten im Durchschnitt etwa 10 Jahre früher eine Dystonie entwickelten als Musikern ohne derartige Begleiterkrankungen. Dies weist auf die wichtige Rolle psychopathologischer Faktoren als Trigger der Musikerdystonie hin.

Zusammenfassend belegt die vorliegende These das Vorliegen psychopathologischer Befunde bei ca. 50% der Musiker mit Dystonien. Patienten mit oder ohne psychiatrische Komorbiditäten unterschieden sich zwar nicht in der motorischen Performanz beim Spielen des Instruments, aber die Ergebnisse zeigen, dass psychopathologische Faktoren die Entwicklung einer Dystonie auslösen oder zumindest beschleunigen können. Die vorliegende These unterstützt das Konzept gemeinsamer neurobiologischer Netzwerke für motorische und psychopathologische Symptome bei der Musikerdystonie.

INTRODUCTION

Introduction

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1 DYSTONIA

1.1 Historical overview The term “dystonia” was firstly used in 1911, by the German neurologist Hermann Oppenheim. 1 It derives from the Greek word δυσ-τονία (δυσ-/dys- = bad, abnormal, misfortune, dysfunctional, and τόνος/tonos = tone, tension), which means impairment of muscle tone or abnormal tonicity. Before Oppenheim, terminology such as “athetosis” (Barraquer Roviralta, 1897), “tonic cramps” (Schwalbe, 1907), “torsion neurosis” (Ziehen, 1911) and “progressive torsion spasm” (Flatau & Sterling, 1911) had been used for diagnosing dystonic symptoms. Oppenheim’s initial term was “dystonia musculorum deformans” (Oppenheim, 1911). However as dystonia is not characterised by muscle disorders the shortened term was preferred (Flatau & Sterling, 1911; Stacy, 2007). Since the beginning of the 20th century neurologists have theorised about a possible genetic predisposition for the condition, and a link between dystonic symptoms and psychiatric diseases (Schwalbe, 1907). Finally, Ziehen (1911) emphasised the organic origin of dystonia and argued that dystonic symptoms are exacerbated during action or emotional excitement. Records of focal task-specific dystonias, the main topic of the current work, date back to the beginning of 18th century. A detailed description of writer’s cramp was given in Ramazzini’s treatise in 1713 (Ramazzini, 1964). Writer’s cramp was initially termed “scrivener’s palsy” by Solly in 1864 (Frucht, 2014; Pearce, 2005), whereas in the late 19th century terms such as “functional” or “neuroses” were also used, as neurologists believed that focal task-specific dystonias were not purely psychologically-based (Frucht, 2014; Marsden & Sheehy, 1990; Torres-Russotto & Perlmutter, 2008). 1.2 Clinical characteristics Dystonia is a neurological movement disorder characterised by muscular overflow, and by sustained and repetitive involuntary co-contractions of agonist and antagonist pairs of muscles. Prolonged symptoms lead to abnormal, frequently stereotyped body postures often accompanied by tremor and pain. However, phenomenology and severity vary: symptoms may affect the entire body (generalised) or a single body part (focal) and can appear either at rest or during the execution of specific motor tasks. Symptoms in some focal dystonias are frequently reduced when using sensory tricks (“geste antagoniste”), e.g. touching the affected body area (Hallett, 2011; Lin & Hallett, 2009; Tanabe et al., 2009). 1 Hermann Oppenheim (1 January 1858 - 5 May 1919) was a pioneering neurologist in Germany. He completed his medical studies at the Universities of Berlin, Göttingen and Bonn. In 1891 Oppenheim established a private hospital in Berlin, and in 1894 he wrote a textbook titled Lehrbuch der Nervenkrankheiten für Ärzte und Studierende, which became a standard resource in the field of neurology.

Introduction

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Definition Over the last three decades, a single definition established by the Dystonia Medical Research Foundation has been used: “Dystonia is a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures” (Fahn, 1988). However, an updated definition has been recently introduced by Albanese et al. (2013):

“Dystonia is a movement disorder characterised by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic

movements are typically patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation”.

1.3 Classification Dystonia is traditionally classified along three main axes: aetiology, age at onset and body distribution (Albanese et al., 2011; Fahn, 2011). Aetiology of dystonia is mainly sub-classified as primary (idiopathic) and secondary (symptomatic). Primary dystonia is diagnosed when symptoms occur spontaneously and no other clinical signs (apart from tremor) or associated diseases are identifiable. In primary dystonia no structural abnormalities of the central nervous system (CNS) are observed, and its cause is mainly unknown. However in some forms, genetic predispositions are involved (Klein, 2014). Secondary dystonia is the occurrence of dystonic symptoms as a consequence of certain neurological conditions (e.g. brain injury, tumour, drug side-effect) or psychological disturbances (i.e. psychogenic dystonia) (Quartarone et al., 2009). Age at onset, which is sub-classified mainly as early- and late-onset, provides information about the cause and the prognostics (Greene et al., 1995). For example, a childhood diagnosis of focal dystonia is more likely to be associated with the condition spreading to multiple parts of the body. In contrast, late-onset or adult-onset focal dystonia (in patients mainly over the age of 25) may involve only limited progression to neighbouring body regions (Fahn et al., 1998). Body distribution indicates the affected body locations. Focal dystonia, which is the most common form, affects only one region (e.g. blepharospasm, cervical, writer’s cramp, musician’s cramp). Segmental dystonia applies when two or more related parts are affected (e.g. cranial dystonia, bi-brachial dystonia). Hemidystonia involves one side of the body and generalised dystonia affects the trunk together with the upper or the lower limbs. An updated classification based on two axes (clinical features and aetiology) has recently been proposed (see Albanese et al., 2013). However, due to the fact that the updated terminology has not yet been widely adapted, the traditional classification has been used throughout the present work.

Introduction

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1.4 Epidemiology and pathophysiology A recent meta-analysis by Steeves et al. (2012) revealed a prevalence of primary dystonia of 16.4 per 100,000 and a prevalence for focal and segmental dystonia specifically of 15.4 per 100,000 people. The authors suggested that the prevalence of dystonia increases with age whereas other studies have also indicated that men may develop dystonia at an earlier age (ESDE, 2000; Marras et al., 2007; Matsumoto et al., 2003). Interestingly, different epidemiological studies have found variability across populations. For instance, the prevalence of primary dystonia in Iceland was reported at 37.1 (Asgeirsson et al., 2006) compared to 15.2 per 100,000 people (Sugawara et al., 2006) in Northern Japan. Differences across populations have also been found in terms of the break-down across different subtypes of dystonia. For example, in Japan a higher prevalence has been reported for blepharospasm in comparison to cervical dystonia, whereas the opposite has been reported in Europe (Matsumoto et al., 2003). In order to clarify the underlying causes of these reported population differences (e.g. genetics, diagnostic criteria), further studies should be conducted based on common methodological approaches. The pathophysiology of dystonia is multifactorial and still not fully understood. It is related to impaired inhibition of motor and sensory pathways (Defazio et al., 2007; Garibotto et al., 2011; Hallett, 2011; Quartarone et al., 2008; Tinazzi et al., 2009), however the main pathogenic mechanism seems to consist of an imbalance between direct and indirect pathways of the basal ganglia (Berardelli et al., 1998; Defazio et al., 2007; Hallett, 2006; Neychev et al., 2011; Quartarone & Hallett, 2013). The pathogenesis of dystonia has also been associated with sensory dysfunction (Fiorio et al., 2007, 2008; Ghilardi et al., 2003; Molloy et al., 2003; Peller et al., 2006), structural abnormalities of the basal ganglia (Black et al., 1998; Defazio et al., 2007; Draganski et al., 2003; Etgen et al., 2006; Garraux et al., 2004; Peller et al., 2006) and abnormalities of the cerebellothalamocortical circuit (Argyelan et al., 2009; Eidelberg et al., 1998; Tanabe et al., 2009), among other factors. Finally, some forms of dystonia are associated with genetic abnormalities classified as DYT loci, or with a failure of dopamine synthesis caused by mutations in specific genes (Klein, 2014; Malek et al., 2015). Further details of the pathophysiology of focal dystonia, the main topic of the current work, are provided in section 2.4.

Introduction

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2 FOCAL DYSTONIA IN MUSICIANS

As well as enjoying the magical world of emotions evoked by listening to a Liszt etude, a Paganini caprice, or the flute sonata by Prokofiev, it is always impressive to observe the incredible fine motor abilities of accomplished musicians. The development of such motor skills requires long-term learning and practice from early childhood. As a result, life-long adaptations of the nervous system render musicians to be one of the best models for investigating motor learning effects and their consequences (Münte et al., 2002). However, pushing motor functions to their limits is not always without cost. One of the most severe motor disorders which can affect musicians’ fine motor control is focal dystonia. Focal dystonia in musicians (FDM), also known as musician’s dystonia or musician’s cramp, has been described since the beginning of 19th century. One of the most famous cases was the Romantic-era pianist and composer Robert Schumann (1810-1856), who developed dystonia in the middle finger of his right hand (Altenmüller, 2005). 2.1 Clinical features and classification FDM is, in most cases, a primary dystonia developing without pain and characterised by muscular incoordination and loss of voluntary motor control whilst playing an instrument. Prolonged symptoms lead to abnormal posture, which can be accompanied by co-contraction of the antagonistic muscle pairs while playing the instrument. It mostly affects one region (focal) of the body, and is largely characterised by two features: i) task specificity, which means that symptoms are triggered during the execution of specific activities (i.e. while playing a musical instrument) and ii) the presence of an effective sensory trick, an immediate improvement of the symptoms by changing the sensory input to the affected region (e.g. wearing a glove on an affected hand) (Altenmüller & Janusch, 2009, 2010; Aránguiz et al., 2011; Conti et al., 2008). FDM is mainly sub-classified as limb dystonia or embouchure dystonia (Altenmüller, 2003; Frucht et al., 2004; Lederman, 1991). In limb dystonia the most affected body regions are the upper limbs (e.g. finger[s], hand, wrist or arm). However, there are also rare reports of musicians affected in the lower limbs, for example a death metal drummer in the right thigh (Lee & Altenmüller, 2014). Hand dystonia is frequently characterised by an involuntary flexion of the affected finger(s). However, extension or a combination of flexion and extension may occur as well. Dystonia affecting only one finger is more likely to spread to adjacent fingers than to a more distant one (Conti et al., 2008; Frucht, 2009). In embouchure dystonia, facial, cervical and tongue muscles are affected; lip- and/or breathing incoordination are also common. Early symptoms are characterised by a lack of fine motor control in already well-trained movements while performing (Figure 1).

Introduction

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2.2 Epidemiology and aetiology The prevalence of FDM is estimated as 1% of musicians. It affects mostly male musicians (male to female ratio is 4:1) and the age at onset varies from 18 to 60 years with a mean age in the mid-30s (Altenmüller 2003; Altenmüller & Jabusch, 2010; Jabusch & Altenmüller 2006b; Lim et al., 2003). According to a recent investigation, about one fifth of affected musicians tend to change profession (Lee et al., 2015). Alternatively, less severely affected musicians often either select repertoire that does not trigger their dystonia or switch from solo performance to instrumental teaching. Other epidemiological studies have shown that several environmental factors can further explain the aetiology of dystonia. For example, professional classical musicians are found to be at much higher risk than jazz, rock, pop or other improvising musicians. The classical repertoire requires reproduction of predefined temporo-spatial fine motor patterns with temporal accuracy in a range of milliseconds. In contrast, other musical genres such as jazz, rock or folk require a more free-style improvised manner of performance and interpretation. Furthermore, musicians playing high-registered instruments (e.g. violin) are more frequently affected than those playing instruments with a lower register (e.g. double bass) (Jabusch & Altenmüller, 2006a, 2006b). With respect to localisation, pianists and guitarists are more frequently affected on the right hand whereas violinists tend to suffer on the left hand. These findings suggest that the higher the temporo-spatial sensorimotor performance demands for a body region, the higher the risk of developing dystonia (Altenmüller & Jabusch, 2010). Finally, a few studies focusing on the psychopathology of musicians with dystonia have reported elevated levels of anxiety and perfectionism (Altenmüller & Jabusch, 2009; Enders et al., 2011; Jabusch et al., 2004b). The authors suggested that abnormal psychological features could additionally contribute to the

Fig. 1. Typical dystonic postures in musicians with hand and embouchure dystonia. Figure from Jabusch & Altenmüller, (2006a). Reprinted with permission from the authors.

Introduction

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manifestation of dystonia in musicians (for more details concerning psychological conditions associated with FDM see section 3.2). 2.3 Genetics and heredity Genetic predispositions have been found to be associated mainly with non-focal primary forms of dystonia such as early onset, dopa-responsiveness, myoclonus, and paroxysmal dystonias. These disorders have been labelled as “DYT” loci followed by a number indicating the chronological order of the discovery and the phenotype (e.g. DYT1 - early-onset torsion dystonia). Recently Marras et al. (2012) proposed an updated coding system which combined the main clinical feature (“DYT”) and the gene name or chromosome locus (e.g. DYT-TOR1A for early-onset generalised dystonia). This system, which provides a more comprehensive classification, is divided mainly into isolated dystonias (early-onset generalised dystonia, adolescent-onset dystonia of mixed type and adult-onset cranial-cervical dystonia) and into combined dystonias (dystonia plus parkinsonism or myoclonus, or paroxysmal dystonia plus other dyskinesia). In contrast, to the above forms of dystonia, focal task-specific dystonias such as FDM or writer’s cramp are much more rarely related to genetic abnormalities. However, investigations support the argument that hereditary factors could contribute to the development of focal dystonia in a considerable proportion of patients. A study by Stojanović et al. (1995) investigated first-degree relatives of 43 patients with focal dystonia including torticollis, blepharospasm and writer’s cramp. The authors found that 23% of patients had relatives affected by related disorders. A similar study, which investigated 56 patients with blepharospasm, found a positive family history in 27% of cases (Defazio et al., 2006). The manifestation of FDM also seems to have a hereditary link. Altenmüller (2003) reported a positive family history in about 10% of affected musicians. A more recent investigation, focusing on genetic predisposition, investigated 28 families of musicians with dystonia. Half of those patients reported positive family history (FH+) whereas the rest reported no family history at all (FH-). Surprisingly, the study indicated that 36% of the FH- patients also had relatives affected by focal dystonia. Finally, the same authors suggested that in at least some cases, FDM may have a shared underlying genetic cause with other forms of task-specific dystonia (Schmidt et al., 2009). 2.4 Pathophysiology 2.4.1 Structural and functional abnormalities

The pathophysiology of focal dystonia remains not fully understood. There are some contradictory results which could be explained either by methodological or interpretational differences, or by the different subtypes of dystonia being investigated. Most imaging studies

Introduction

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find functional abnormalities of the basal ganglia-cortical loops. However a number of studies have suggested structural abnormalities in different brain regions as well (Bhatia & Marsden, 1994; Fross et al., 1987; Prell at el., 2013; Rondot et al., 2001; Rutledge et al., 1988; Zoons et al., 2011). Magnetic resonance imaging (MRI) studies in patients with cranial or hand dystonia revealed a 10% increase in size of the putamen (Black et al., 1998) whereas Garraux et al. (2004) found a bilateral grey matter increase in the hand area of primary sensorimotor cortex in patients with hand dystonia. These findings are in contrast to the study of Delmaire et al. (2007), which found a reduced volume in the same areas in patients with writer’s cramp. In addition, Delmaire et al. (2007) reported a grey matter decrease in the thalamus and cerebellum. A reduction in grey matter, which was more pronounced after a 5-year follow up, was also found in the left caudate head and putamen, and in the premotor and primary sensorimotor cortices bilaterally in patients with cervical dystonia (Pantano et al., 2011). Egger et al. (2007) examined different types of primary dystonia (generalised, cervical, and hand dystonia) and suggested that a common pattern of grey matter alterations exists in patients with dystonia. One of the very few imaging studies of pianists with right hand dystonia indicated an increase in grey matter volume in the ipsilateral middle putamen in comparison to healthy pianists. The authors further concluded that the lower the timing precision in piano execution, the higher the grey matter volume in the middle putamen bilaterally (Granert et al., 2011). Finally, increasing evidence suggests that abnormal activity of the cerebellum could also be involved in the pathophysiology of dystonia (Avanzino & Abbruzzese, 2012; Lee et al., 2013; Sadnicka et al., 2012). For instance, a transcranial magnetic stimulation (TMS) study found reduced cerebellar modulation of the motor cortex excitability in patients with focal dystonia (Brighina et al., 2009). In addition to investigation of structural abnormalities, several functional neuroimaging studies have been conducted in order to probe neuronal activity in specific brain regions. Early positron emission tomography (PET) measurements demonstrated functional abnormalities of the putamen and other components of basal ganglia-cortical circuits (Karbe et al., 1992; Magyar-Lehmann et al., 1997; Perlmutter & Raichle, 1984; Stoessl et al., 1986). A functional magnetic resonance imaging (fMRI) study conducted in patients with writer’s cramp revealed bilateral enhanced activity of the putamen, caudate nucleus, internal globus pallidus and lateral thalamus during the discrimination of tactile stimuli (Peller et al., 2006). Two PET studies have shown deficient activity in the sensorimotor cortex in writer’s cramp patients during a motor task paradigm (Ibáñez et al., 1999) and during sensory stimulation (Tempel & Perlmutter, 1993). The first study additionally reported a reduced correlation between premotor cortex and putamen activity, whereas the second found a reduced response in the supplementary motor area. Lower signals in sensorimotor cortices have also been reported in patients with laryngeal dystonia (Haslinger et al., 2005), whereas in patients with

Introduction

14

hand dystonia a persistent abnormal signal in the striatum has been observed immediately following the end of a specific finger task (Blood et al., 2004). Another fMRI study in writer’s cramp patients showed greater ipsilateral cerebellar activation, and an increased activation of basal ganglia output via thalamus to motor and premotor cortical regions during writing. The authors argued that this was evidence for the existence of dysfunctional inhibition of the motor cortex leading to dystonic symptoms (Preibisch et al., 2001). Finally, fMRI studies have also been conducted in musicians with focal dystonia. For instance, affected guitarists revealed greater activation of the contralateral primary sensorimotor cortex while performing with their musical instruments (Pujol et al., 2000). The authors concluded that there is an abnormal recruitment of cortical areas during control of task-induced movements. Recent investigations have also revealed an over-activation of somatotopic face representations of primary sensorimotor and premotor cortex bilaterally in musicians with embouchure dystonia (Haslinger et al., 2010), whereas guitarists with hand dystonia exhibited irregular activation patterns in the motor-association system, with dysfunction primarily in premotor regions and cerebellum (Kadota et al., 2010). 2.4.2 Dysfunction of the Basal Ganglia The basal ganglia are subcortical nuclei located bilaterally in the forebrain. They comprise the striatum (which consists of the caudate nucleus, the putamen, and the ventral striatum, which also includes the nucleus accumbens), the globus pallidus, the substantia nigra (pars reticulata and pars compacta) and the subthalamic nucleus (Kandel et al., 2000). The basal ganglia have been associated with the tuning of fine motor control of voluntary movements, motor learning, initiation and termination of voluntary movements and behavioural and emotional functions (Helie et al., 2013; Hikosaka et al., 1995; Mink, 1996). The origin of focal dystonia has been suggested to be an over-activity of the direct striatopallidal pathway of the basal ganglia (Berardelli et al., 1998; Defazio et al., 2007; Hallett, 2004, 2006; Zeuner et al., 2015). As a consequence, a reduced output of the internal globus pallidus (GPi) results in over-excitation of the thalamic input to the cortical regions (Defazio et al., 2007). Several studies have shown that the dopaminergic system may be affected in patients with focal dystonia. The dopaminergic projection from the substantia nigra pars compacta (SNc) to the striatum differentially affects the two striatal outputs (direct and indirect pathways). Striatal neurons involved in the direct pathway (from putamen to GPi) have D1 dopamine receptors responsible for facilitating transition, whereas striatal neurons involved in the indirect pathway (from putamen to external globus pallidus [GPe]) have D2 receptors involved in the reduction of transition (Kandel et al., 2000). A PET study has shown that patients with focal dystonia have decreased (29%) dopamine D2 receptors in the putamen (Perlmutter et al., 1997). Similar findings have also been reported by Naumann (1998) in

Introduction

15

patients with idiopathic cervical dystonia. The authors concluded that dystonia resulted from disturbances of the indirect pathway of the basal ganglia. A reduced striatal D2 receptor in the caudate and putamen has also been reported in patients with idiopathic torsion dystonia (Asanuma et al., 2005). 2.4.3 Loss of inhibition Movement excitability, muscular overflow of activity in adjacent muscles, and muscular co-contractions in patients with focal dystonia have been explained as consequences of loss of inhibition. However, it remains unclear whether loss of inhibition indicates another cause of dystonia, or is rather an adaptive reaction to the already-manifested dystonic symptoms (Hallett, 2006; Quartarone & Hallett, 2013; Torres-Rossotto & Perlmutter, 2008). Studies based on TMS have repeatedly indicated reduced cortical inhibitions in patients with focal dystonia. For instance, a reduction in both sides (symptomatic and asymptomatic) of intracortical inhibition has been reported by Ridding et al. (1995) and Rona et al. (1998). In contrast, Chen et al. (1997) reported a reduction of intracortical inhibition only in the symptomatic hemisphere during voluntary muscle activation in writer’s cramp. Impaired modulation of intracortical inhibition during the performance of a phasic index finger flexion task has also been reported by Stinear and Byblow (2004a) in patients with focal hand dystonia (FHD). Magnetic resonance spectroscopy (MRS) indicated a reduction in γ-Aminobutyric acid (GABA), a major inhibitory neurotransmitter, in the sensorimotor cortex and lentiform nuclei in patients with focal dystonia. GABA was significantly decreased in the contralateral side to the affected hand (Levy & Hallett, 2002). Finally, lack of inhibition in patients with writer’s cramp has also been demonstrated based on elevated excitability at the corticospinal level during stimulation (Quartarone et al., 2003). Another factor found to be related to focal dystonia is the loss of surround inhibition. In healthy subjects, neighbouring muscles not directly engaged in a specific movement task become actively inhibited (Hallett, 2011; Sohn & Hallett, 2004b; Stinear & Byblow, 2004b). Numerous studies have demonstrated that this function is abnormal in patients with focal dystonia (Beck et al., 2008, 2009; Hallett, 2011; Quartarone et al., 2005; Sohn & Hallett, 2004a). Rosenkranz et al. (2005) investigated pathophysiological differences between musician’s and writer’s cramp. The study involved the stimulation of a single muscle of one hand with a vibration, while the corticospinal excitability of the stimulated and other muscles of both hands were tested with TMS. In healthy non-musicians the sensory stimulus of the vibrated muscle evoked potentials of greater amplitude and demonstrated a decrease in short-latency intracortical inhibition. The pattern in muscles of the non-vibrated hand was exactly the opposite. These effects were abnormal in both focal dystonia groups, and were explained as being due to a loss of surround inhibition. The authors suggested that the extensive practice

Introduction

16

required for music performance may lead to FDM patients undergoing abnormal changes in the organisation of the motor cortex. 2.4.4 Maladaptive plasticity and sensory dysfunction Physiological investigations have indicated that abnormal plasticity, mainly in sensory and motor areas, could contribute to the pathogenesis of focal dystonia (Hallett, 2006; Quartarone & Hallett, 2013; Quartarone & Pisani, 2011; Quartarone et al., 2003, 2006). A pioneering animal study in focal dystonia was conducted by Byl and Merzenitch (1996). Monkeys were trained to perform a long repetitive stereotypical task until their movement accuracy declined to a level typical of impairments seen in hand dystonia. As a result of the reduced fine motor control, cortical recordings in the sensorimotor cortex showed a degradation of cortical digit representations of sensory information. These findings strongly support the idea that environmental factors related to repetitive movement activities can impair sensory receptive fields and promote the manifestation of focal dystonia. A study combining TMS and transcranial direct-current stimulation (TDCS) found impaired homeostatic control (corticospinal imbalance between excitation and inhibition) in writer’s cramp patients. The authors suggested maladaptive plasticity of the sensorimotor circuits as an explanatory mechanism (Quartarone et al., 2006). The cause of abnormal plasticity in focal dystonia patients is still debated. It could either be a consequence of the loss of inhibition as discussed above (Hallett, 2011), or result from extensive repetitive tasks (Torres-Russoto & Perlmutter, 2008). Investigations of sensory dysfunction indicated that focal dystonia is not only characterised by motor deficits but is also a disorder involving sensory abnormalities (Hallett, 2011). Magneto-encephalographic (MEG) studies found bilaterally abnormal somatotopic organisation of the hand in patients with unilateral hand dystonia (Nelson et al., 2001).

Further studies focusing on FHD have also reported greater temporal and spatial discrimination thresholds in both affected and unaffected body regions (Bara-Jimenez et al., 2000; Bradley et al., 2010; Fiorio et al., 2003; Molloy et al., 2003; Sanger et al., 2001; Scontrini et al., 2009; Tamura et al., 2008). Interestingly, Molloy et al. (2003) reported increased spatial discrimination thresholds for focal dystonia patients (i.e. hand dystonia, blepharospasm and cervical dystonia) but not for generalised DYT1 dystonia patients, suggesting that alterations of sensory processing have a primary pathophysiological role in the manifestation of focal dystonia. A magnetic source imaging study, which compared hand-affected FDM patients with healthy musicians (HM), indicated that patients, in comparison to HM, were characterised by an overlapping of the digit representations in the symptomatic somatosensory cortex. This effect was less pronounced in the contralateral non-affected hand (Elbert et al., 1998; Münte et al., 2002). Finally, more recent EEG studies reported that

Introduction

17

pianists with focal dystonia show deficient phase synchronisation between those cortical regions involved in preparation of upcoming motor movements (Ruiz et al., 2009, 2011). With regard to the many, partially contradictory pathophysiological findings, the extent to which they contribute to the genesis of dystonia, as opposed to being consequences of it, remains uncertain. Taking all the above epidemiological and pathophysiological findings together, FDM is clearly a complex neurological movement disorder, characterised by a multifactorial aetiology. Triggering factors contributing to the manifestation of dystonia are schematically represented in Figure 2. 2.5 Treatment methods Due to the multi-aetiological cause and the limited pathophysiological understanding of focal dystonia, a range of treatment methods are used in clinical practice and only few randomised prospective studies exist. Oral medications such as anticholinergics (e.g. trihexyphenidyl), dopaminergic and GABAergic drugs (e.g. benzodiazepines or baclofen) are often used. In the case of musician’s dystonia, trihexyphenidyl has been reported as one of the most effective medications (Jabusch et al., 2005). However, sometimes these substances are not well-tolerated, giving rise to side-effects. Another method used in FHD dystonia is the injection of botulinum toxin (BTX) type A in the dystonic muscle(s) (Schuele et al., 2005). BTX reduces muscular activity and alleviates cramping and abnormal postures (Filippi et al., 1993). However, its effect is temporary, lasting from three to six months, and muscular weakness

Fig. 2. Triggering factors contributing to the manifestation of FDM. (Figure from Altenmüller & Jabusch (2010). Original source from Jabusch & Altenmüller (2006a). Reprinted with permission from the authors.

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18

may cause deterioration of playing ability (Cole et al., 1995). Other effective treatments with long-term effects include retraining of the sensorimotor system (Altenmüller & Jabusch, 2010; Byl & McKenzie, 2000; Candia et al., 2003). Retraining frequently involves prolonged training periods which can last up to two years. These therapies focus on the restoration of hand sensory function, disorders of which have been explained above. Retraining and BTX injections have been reported as the most effective treatment approaches in musicians with dystonia (Hallett et al., 2009; Schuele et al., 2005; van Vugt et al., 2014). Further treatment approaches include the immobilisation of the affected limb with specially designed splints, adjustment of performance demands (e.g. selection of a repertoire which does not trigger dystonia), ergonomic adaptations (e.g. instrument modifications) and psychological supervision (Altenmüller & Jabusch, 2010; Frucht, 2009; Pesenti et al., 2004; Priori et al., 2001). Surgical treatments, such as a stereotactic nucleus ventrooralis thalamotomy (Taira & Hori, 2003) or deep brain stimulation have also been used (Tisch et al., 2006a, b). However, surgical approaches are rather rare and are mainly used in more disabling generalised dystonias (Torres-Russotto & Perlmutter, 2008). In summary, treatment for focal dystonia is mostly symptomatic and there is still an urgent need to improve treatment efficacy.

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3 PSYCHO-PSYCHIATRIC FEATURES

3.1 Psychopathology in primary focal dystonia Since the historical division between neurology and psychiatry, the treatment of movement disorders has fallen within the purview of neurologists. However, over the last two decades a plethora of studies have revealed that common movement disorders such as Parkinson's disease, idiopathic dystonia, and Huntington's disease are accompanied by non-motor features such as depression, anxiety, specific phobias, various obsessions, and cognitive deficits in certain domains (Aarsland et al., 1999; Cummins et al., 2015; Gündel et al., 2001, 2003; Halstead et al., 1994; Lennox & Lennox, 2002; Paulsen et al., 2001; Schröder et al., 2006, 2010; Stamelou et al., 2012). Ron (2009) suggested that:

“Dysfunction of basal ganglia-thalamo-cortical connectivity extends to limbic loops involving the amygdala and orbitofrontal cortex that elicit or suppress motor activity in response to emotions”.

As explained above, dysfunction of the cortico-striatal-thalamo-cortical (cortico-basal ganglia-cortical) circuit form part of the pathophysiology of primary dystonia (Hallett, 2006; Quartarone & Hallett, 2013). However, this circuit has also been reported to support non-motor function, such as sensory, cognitive, learning and reward processing. The basal ganglia in general are involved in many cognitive, behavioural and emotional functions (Everitt & Robbins, 2005; Graybiel, 2005; Helie et al., 2013; Hikosaka et al., 1995; Mink, 1996; Shatner et al., 2003; Stamelou et al., 2012; Yin & Knowlton, 2006). There is evidence that the cortico-striatal-thalamo-cortical circuits and specifically cortical-limbic-striatal and basal ganglia dysfunction play an originating role in depression (Alexander et al., 1990; Stefurak et al., 2003). Cavallaro et al. (2002) hypothesised that disturbances of the striato-thalamo-cortical circuitry may be commonly associated with idiopathic focal dystonia and obsessive-compulsive symptoms. A further neurobiological link between focal dystonia and various psychiatric disorders may be the loss of inhibition. As is the case with focal dystonia, neuroimaging studies have reported over-excitation in several cortical and subcortical brain regions in patients with depression (Fitzgerald et al., 2008; Savitz & Drevets, 2009). Those authors suggested that loss of inhibition could be associated with depression, which is an argument supported by studies in animal models (Hasler & Northoff, 2011). Numerous studies exploring the psychopathology of focal dystonia have reported psychiatric disorders or psychological instabilities in a considerable proportion of patients (Kuyper et al., 2011; Stamelou et al., 2012). Fabbrini et al. (2010) investigated psychiatric features in 89 patients diagnosed with primary focal dystonia. All patients were interviewed based on the

Introduction

20

DSM-IV2 and were therefore evaluated for possible obsessive-compulsive disorders (OCD), anxiety and depression based on standardised psycho-diagnostic instruments. 57.3% of the patients were diagnosed with additional psychiatric disorders such as depressive conditions. Moreover, the authors proposed that these features were supplementary to the motor dysfunction rather than a psychoreactive phenomenon. Psychiatric comorbidities have also been examined in a large group of patients with spasmodic torticollis (n = 116). Social phobia was reported in 41.3% of the patients, whereas depressive coping behaviour was found to be the main predictor of this comorbidity (Gündel et al., 2001, 2003). Patients with spasmodic torticollis revealed 3.7 times increased risk for psychiatric comorbidities related to anxiety and depression. This investigation is remarkable since other patients (specifically diagnosed with alopecia areata), with similar physical appearance and body image satisfaction, were used as controls. Matched criteria associated with body image between patients and controls ensured that any psychiatric comorbidity would not be a secondary effect after the onset of the condition. Further studies investigating psychopathology in patients with spasmodic torticollis reported psychopathology in about half of the patients. The most frequently detected features were depressive disorder and anxiety (Moraru et al., 2002; Wenzel et al., 1998). Anxious personality disorders related to obsessive-compulsive and avoidant behaviour were also found in 32.6% of 86 patients diagnosed with primary focal dystonia (Lencer et al., 2009). Finally, one study by Scheidt et al. (1996), who found psychopathology in more than 50% of patients with spasmodic torticollis, reported an exacerbation of psychopathology under stressful psychosocial life events. Gündel et al. (2007), who detected psychiatric comorbidities in a considerable proportion of patients suffering from spasmodic dysphonia, found a positive correlation between the level of the psychiatric comorbidities (i.e. depression and anxiety) and the severity of the disorder. These authors suggested that this correlation may be a result of a strong interaction between the somatic complaints of the specific type of dystonia and the psychiatric complaints. Only a few studies have reported an association between psychiatric disorders and the severity of dystonia (Lewis et al., 2008; Naber et al., 1998; Scheidt et al., 1996). Cavallaro et al. (2002) examined 76 patients affected by idiopathic focal dystonia. 19.7% of them were additionally affected by OCD with 13.8% having OCD-related family history. The authors proposed a common pathophysiological mechanism in OCD and focal dystonia; other studies have suggested that dystonia and OCD are derived from the same dysfunctional circuits of the basal ganglia (McNeill, 2003). Recently, Lehn et al. (2014), who investigated psychopathology in 103 patients with focal dystonia, found increased levels of OCD followed

2 The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), is a standardised classification manual used by clinicians, therapists, researchers, and others for diagnosing mental health disorders in children and adults. The DSM-IV is published by the American Psychiatric Association.

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21

by anxiety and depression. The authors also showed that anxiety features may have better discriminatory power to distinguish patients with and without psychopathology. Higher prevalence of OCD in patients with focal dystonia has been also reported by Bihari et al. (1992), Barahona-Corrêa et al. (2011) and Mula et al. (2012). Finally, in addition to the psychiatric conditions in patients with dystonia, several other mild non-motor features, such as cognitive and emotional impairments (Aleman et al., 2009; Bugalho et al., 2008; Jahanshahi et al., 2003; Nikolova et al., 2011) or sleep disturbances (Avanzino et al., 2010; Trotti et al., 2009; Wein & Golubev, 1979) have been reported (for reviews, see Kuyper et al. [2011] and Stamelou et al. [2012]). Taken together, the studies mentioned above clearly reveal that a considerable proportion of patients with focal dystonia (~50%) are additionally diagnosed with psychopathology. Depression, OCD, anxiety and specific phobias seem to be the most frequent features accompanying motor symptoms (Stamelou et al., 2012). 3.2 Psychopathology in Musician’s Dystonia Only a few studies have focused on psychopathology in musician’s dystonia. Jabusch et al. (2004b) examined psychological conditions in 20 FDM patients, 20 musicians with chronic pain, and 30 HM. Personality features (e.g. somatic complains, emotionality, irritability) were examined based on the Freiburg Personality Inventory (FPI-R) (Fahrenberg et al., 1994), while features such as self-concept of abilities and control orientations were tested using the Competence and Control Orientation (QCC) inventory (Krampen, 1991). Finally a self-designed questionnaire was constructed in order to assess perfectionism and anxiety. Both patient groups revealed elevated levels of anxiety in comparison to healthy controls, with FDM patients exhibiting more perfectionism. The authors speculated that psychological conditions in musicians with dystonia and in those with chronic pain pre-dated the onset of the main disease. Another study conducted by the same laboratory focused exclusively on anxiety disorders (e.g. social phobia, agoraphobia) (Jabusch & Altenmüller, 2004). Again, FDM (n = 20) and chronic pain (n = 20) groups were compared with healthy controls (n = 30). All participants filled out an investigator-designed questionnaire. Findings indicated that social phobias and specific phobias, which seemed to appear before the onset of dystonia, were more prominent in FDM patients. Finally, a more recent investigation explored psychopathology in musicians with dystonia by comparing 44 FDM patients with 45 HM and 44 healthy non-musicians (Enders et al., 2011). Anxiety and personality traits were examined using the NEO Five-Factor Inventory (NEO-FFI) (Costa & McCrae, 1992) and the State-Trait Anxiety Inventory (STAI) (Spielberger & Gorsuch, 1983). The FDM patients exhibited increased levels of neuroticism and general state and trait anxiety in comparison to the two control groups. As with previous studies, the authors suggested that these psychological conditions were not psychoreactive phenomena.

Introduction

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The above-mentioned studies suggest that FDM patients are characterised primarily by elevated levels of anxiety, perfectionism and neuroticism. If we consider that neuroticism is a personality trait largely involving anxiety, fear, worry, guilt, and depressed mood (Matthews et al., 2003; Thompson, 2008) we can conclude that features related to anxiety and perfectionism - which also seem to pre-date the onset of the disease - can be considered psychiatric comorbidities in musicians with focal dystonia. Increased anxiety has also been reported in many other forms of focal dystonia (Gündel et al., 2001, 2007; Lencer et al., 2009; Moraru et al., 2002), whereas perfectionism may be more related to occupations such as music and sports (Altenmüller & Jabusch, 2009; Gucciardi et al., 2012). Musicians affected with focal dystonia are mostly classical performers. The classical repertoire requires practising and interpreting with maximal temporal and pitch precision. These demands minimise the error rate and consequently maximise the expectation of the performers and audience. In addition, a successful performance often is the “ticket” to the next job (performance). This concept is highly associated with income, carrier-development and the social prestige of the musicians. These factors trigger psychosocial pressure in a reward and punishment context, which may well lead to increased levels of anxiety and perfectionism (Altenmüller & Jabusch, 2010). Jabusch & Altenmüller (2004) suggested that pre-existing anxiety and perfectionism could contribute to the manifestation of dystonia. They claimed that motor disturbances in musicians with increased psychological conditions may be perceived as a threatening element (emotional stress) and therefore could impair emotionally-induced memory consolidation. Emotional memory consolidation relies on noradrenergic activation of the basolateral amygdala (BLA) (Clayton & Williams, 2000; Ferry & McGaugh, 2000; McGaugh, 2000; Packard et al., 1994; Williams et al., 1998), which projects to the primary motor cortex (Sripanidkulchai et al., 1984). Based on animal studies, Bergado et al. (2006) indicated that activation of the BLA also contributes to the reinforcement of neural plasticity. Impairments of this circuit in combination with dysfunctional motor programs may additionally contribute to the manifestation of dystonia (Figure 3). To summarise, the authors suggested that emotionally-induced motor memory consolidation could contribute to the development of dystonia (Altenmüller & Jabusch, 2009). Animal model studies have similarly demonstrated that pathologies of the motor system could be influenced by stress and glucocorticoids, whereas stress-associated anxiety or emotional changes associated with stress can also affect skilled fine motor movements (Kirkland et al., 2008; Metz, 2007; Metz et al., 2001; 2003, 2005; Smith et al., 2008; Zucchi et al., 2009). Making music in professional contexts requires extreme fine motor skills under emotionally charged conditions. Therefore exploring psychopathology in musicians with focal dystonia may contribute to the understanding of the common neuro(psycho)biological links between focal dystonia and various psychiatric disorders.

Introduction

23

Fig. 3. Emotionally-induced memory consolidation in FDM patients with elevated levels of anxiety and perfectionism. Increased norepinephrine release of the basolateral amygdala (BLA), which projects to the primary motor cortex (M1), is a prerequisite for memory-enhancing effects of glucocorticoids. It has been suggested that emotional memory consolidation may contribute to the development of dystonia. However it remains unknown whether modulatory activity of the BLA also has an effect on the basal ganglia circuit (Jabusch & Altenmüller, 2004). GPe = external globus pallidus; PM = premotor cortex; S1 = somatosensory cortex; SMA = supplementary motor area; GPi = internal globus pallidus; STN = subthalamic nucleus. Figure from Jabusch & Altenmüller (2004). Original source from McGaugh (2000). Reprinted with permission from AAAS.

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4 AIMS

Based on previous studies exploring psychopathology in FDM, several questions have been derived for the present thesis:

• Do musicians with dystonia suffer from performance-related trait anxiety and perfectionistic tendencies more frequently than healthy musicians, when assessed with standardised psycho-diagnostic instruments? Could stress-coping strategies also contribute to the understanding of the psychopathology of FDM patients?

• If psychopathology exists among FDM patients, is it associated with all patients or

only with a certain class of them?

• If subgroups do indeed exist, are there any phenomenological or motor outcome differences between patients with and without psychopathology?

• How do patients with and without psychopathology respond to psychosocial stressors?

Is there any impact of psychosocially stressful events on the motor symptoms of FDM patients?

The major aim of the current work was to investigate the psychopathology of musicians with focal dystonia and its possible impact on motor function. The research questions above were addressed in three different studies, each presented in a separate chapter with the following specific objectives:

1. The first study presents an open design exploratory analysis, which investigates the psychological profile of FDM patients. A range of psycho-diagnostic subscales exploring performance-related trait anxiety, perfectionism and stress-coping strategies were used.

2. The second study was conducted in order to assess the feasibility of a complex experimental paradigm designed to examine the effect of stress on motor performance of FDM patients.

3. Finally, the last study examines electrophysiological motor performance features of

FDM patients; firstly, before and after exposure to psychosocially stressful events, and secondly in association with psychopathology.

CHAPTERS

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1

PSYCHOLOGICAL CHARACTERISTICS IN MUSICIAN'S DYSTONIA A NEW DIAGNOSTIC CLASSIFICATION*

Christos I. Ioannou, Eckart Altenmüller

Institute of Music Physiology and Musicians' Medicine, Hannover University of Music, Drama and Media,

Emmichplatz 1, 30175 Hannover, Germany

* The current chapter corresponds to an article already published in the journal Neuropsychologia, 2014, Vol. 61, pp. 80-88.

(doi:10.1016/j.neuropsychologia.2014.05.014)

Author contributions: Experimental design: CII, EA; Clinical examination of patients: EA; Conducting the

experiments, Data acquisition and pre-processing, Statistical analysis: CII; Writing of manuscript: CII; Contribution to the writing and revision of manuscript: EA.

Abstract: Numerous studies suggest that dysfunctional basal ganglia-thalamo-cortical circuits are involved in both movement disorders and psychiatric impairments. The current exploratory investigation explored possible psychological differences, firstly between 24 healthy musicians (HM) and 24 musicians diagnosed with focal dystonia (FDM) (Study I), and secondly among 35 FDM patients only (Study II). Results revealed that FDM patients are six times more likely to exhibit elevated anxiety, perfectionistic and stress characteristics than HM. These psychological conditions might contribute as aggravating risk factors to the development of FDM. However, half of the FDM patients did not demonstrate any signs of anxiety, perfectionism or stress. The findings point to the clear existence of two different psychological profiles among FDM patients. We suggest that this psychological distinction might reflect two different maladaptive processes mediated via different circuits of the cortico-basal ganglia-thalamicloops. The new classification of FDM patients will contribute to the reinforcement of the diagnostic repertoire, necessary for the selection of more specific treatment methods. Keywords: Focal dystonia; musicians; psychological characteristics; diagnostic classify-cation; cluster analysis

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2

OBJECTIVE EVALUATION OF PERFORMANCE STRESS IN MUSICIANS WITH FOCAL DYSTONIA

A CASE SERIES*

Christos I. Ioannoua, Shinichi Furuyaa, b, Eckart Altenmüllera

a Institute of Music Physiology and Musicians' Medicine, Hannover University of Music, Drama and Media,

Emmichplatz 1, 30175 Hannover, Germany b Department of Information and Communication Science Sophia University

4-4 Chiyodaku, Tokyo, Japan

* The current chapter corresponds to an article already in press in the journal of Motor Behavior.

(doi: 10.1080/00222895.2016.1161590)

Author contributions: Experimental design: CII, EA; Clinical examination of patients: EA; Conducting the experiments, Data acquisition and pre-processing, Statistical analysis: CII; Electromyographic analysis: SF;

Writing of manuscript: CII; Contribution to the writing and revision of manuscript: SF, EA.

Abstract: Five musicians suffering from focal dystonia participated in a pilot study which examined the feasibility of an experimental protocol designed to assess musicians’ motor performance under stress. Electrocardiography (ECG), free cortisol levels and subjective assessments were used to monitor alterations of the hypothalamic-pituitary-adrenal (HPA) axis. As measures of motor outcome, temporal variability of finger movements and muscular co-contraction (EMG) of the wrist flexor and extensor were assessed. Findings suggest that the specific experimental design could be successfully applied. Several methodological issues such as carryover effects, the use of free cortisol, the inclusion of a double baseline and the classification of dystonic patients into stress responders and non-responders are analysed and discussed. Keywords: Focal dystonia; motor performance; EMG; ECG; free cortisol; Trier Social Stress Test

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3

THE IMPACT OF STRESS ON MOTOR PERFORMANCE IN SKILLED MUSICIANS SUFFERING FROM FOCAL DYSTONIA

PHYSIOLOGICAL AND PSYCHOLOGICAL CHARACTERISTICS

Christos I. Ioannoua, Shinichi Furuyaa, b, Eckart Altenmüllera

a Institute of Music Physiology and Musicians' Medicine, Hannover University of Music, Drama and Media,

Emmichplatz 1, 30175 Hannover, Germany b Department of Information and Communication Science Sophia University

4-4 Chiyodaku, Tokyo, Japan

* The current chapter corresponds to an article already published in the journal Neuropsychologia, 2016, Vol. 85, pp. 226-236.

(doi: 10.1016/j.neuropsychologia.2016.03.029)

Author contributions: Experimental design: CII, EA; Clinical examination of patients: EA; Conducting the experiments, Data acquisition and pre-processing, Statistical analysis: CII; Electromyographic analysis: SF;

Writing of manuscript: CII; Contribution to the writing and revision of manuscript: SF, EA.

Abstract: Recent investigations have suggested that stress can modulate motor function. However, the impact of stress on motor performance of musicians suffering from focal dystonia (FDM) remains unknown. The current study assessed motor performance in 20 FDM patients and 16 healthy musicians (HM) before and under stress. Stress was manipulated using the Trier Social Stress Test (TSST). Motor performance was evaluated based on analysis of electromyographic (EMG) activity and temporal variability, while electrocardiography (ECG) and the level of free cortisol were used to test for objective alterations of the hypothalamic-pituitary-adrenal (HPA) axis. Finally, the psychological profiles of both groups were analyzed using three psycho-diagnostic standardized questionnaires. Results showed that patients' motor impairments did not change under acute stressful conditions. However, an increase in muscular co-contractions was observed, reflecting a physiological muscular response under stressful conditions. Psycho-diagnostic analysis revealed higher levels of psychological traits related to elevated anxiety, stress and perfectionism in 40% of the patients. Although the motor outcome between those patients and those with an opposing psychological profile did not differ, patients characterized by stressful and perfectionistic personalities had, on average, developed dystonia about ten years earlier than the rest of the patients. The current study suggests that acute stress conditions may not have any direct impact on fine motor control of FDM patients. However psychological traits associated with increased stress, anxiety and perfectionism may have a long-lasting effect on the motor function of affected musicians, by promoting the acceleration or even the triggering of dystonia. Keywords: Focal dystonia in musicians; motor outcome; temporal variability; stress; EMG; ECG; cortisol; psycho-diagnostics

CONCLUSIONS AND OUTLOOK

Conclusions and Outlook

35

CONCLUSIONS

The current thesis explored psychological conditions and their possible impact on motor performance in musicians suffering from focal dystonia. Limitations and questions derived from previous studies exploring psychopathology in FDM patients (see section 4) were investigated in three consecutive studies. Summarising, the first study focused on the exploration of the psychological profile of FDM patients. A cluster analysis indicated that based on specific psychological features related to anxiety, perfectionism and stress, FDM patients can be classified into those with and those without psychopathology (ratio about 1:1). The risk of exhibiting these psychological comorbidities was about six times greater for patients than healthy controls. Most previous studies exploring psychopathology in other forms of focal dystonia have indicated that it occurs in a considerable proportion of, but not in all patients (for a review see Stamelou et al. [2012]). Our results indicate that FDM patients are characterised by psychological heterogeneity, leading to the suggestion that further exploration and diagnostic classification is needed in FDM. We further conclude that psychological conditions could contribute to the development of dystonia in musicians, and as previous studies also suggested (Enders et al., 2011; Jabusch & Altenmüller, 2004; Stamelou et al., 2012) our findings indicate that psychological conditions are not psychoreactive phenomena. In line with ideas set out by Alexander (1990), Haber and Calzavara (2009), and Ron (2009), the first study suggests that the two subgroups (FDM patients with and without psychopathology) might reflect two different maladaptive processes mediated via different circuits of the cortico-basal ganglia-thalamic loops. Furthermore, we proposed a heuristic model with which individuals could be psychologically evaluated and classified. This model remains useful for experimental procedures and could be further developed into a more comprehensive and standardised psycho-diagnostic protocol in a clinical setting. Finally, the first study suggests that musicians suffering from focal dystonia should be additionally submitted to neurological evaluation with respect to possible psycho-psychiatric comorbidities. A broader neuropsychological diagnosis would help the selection of appropriate therapeutic approaches. The establishment of standardised psycho-diagnostic instruments, suitable for musicians suffering from dystonia, would reinforce the diagnostic repertoire of physicians. The second study was conducted in order to examine the feasibility of a complex experimental paradigm designed to assess musicians’ motor performance before and after stress. According to our knowledge this has never previously been investigated in FDM patients, nor in patients with other forms of focal dystonia. A well-established protocol (TSST, Kirschbaum et al., 1993) designed to induce stress in laboratory conditions, was adapted and


36

alterations of the HPA axis were continuously assessed using physiological measurements (ECG and cortisol analysis). The motor outcome of musicians was also evaluated using EMG analysis and a MIDI-Analysis-System (Jabusch et al., 2004a) which examines the temporal variability of precise finger strokes in scale playing. This pilot analysis indicated the stability of the specific experimental design and provided further methodological insights such us the effective application of a second baseline in order to eliminate carryover effects. On the basis of the study, we suggest that the classification of dystonic patients (or any population which may exhibit psychopathology) into stress responders and non-responders should be based on objective rather than on subjective measurements. The novel experimental design, which was successfully applied, could form a strong scientific tool for further examination of psychophysiological factors in patients suffering from focal dystonia or other movement disorders. The final investigation comprised a combination of the psycho-diagnostic evaluation of the first study and the experimental paradigm of the second study. The main goal was to explain physiological (motor outcome) differences i) between FDM patients with and without psychopathology and ii) under non-stressful versus stressful conditions. Findings showed that FDM patients were characterised by impairments of fine motor control in comparison to HM (Altenmüller & Jabusch, 2009, 2010; Jabusch et al., 2004a). The psycho-diagnostic analysis replicated the results of the first study. However, no motor performance differences were observed between patients with and without psychopathology, suggesting that abnormal psychological conditions have no direct impact on the motor performance of affected musicians. Similarly, FDM patients revealed no alterations of their fine motor control under stress, although an increase in muscular co-contraction activity was observed, which was explained as a normal physical reaction under stressful conditions. Finally, FDM patients indicated greater sensitivity to psychosocial stressors compared to healthy musicians, which could be explained by the increased levels of stress and anxieties in the former group. Beside the fact that no motor outcome differences were found between patients with and without psychopathology, a remarkable finding was that patients with psychopathological comorbidities developed dystonia much earlier (by about ten years) than those without. This could support the idea that common neurobiological networks interact during motor and psychological control. Findings from animal model studies indicating that pathologies of the motor system could be influenced by stress and glucocorticoids (Kirkland et al., 2008; Metz, 2007; Smith et al., 2008; Zucchi et al., 2009) may explain the acceleration of the manifestation of dystonia in patients with psychopathology. The current result could also provide further insights about the pathophysiology of focal dystonia. Our findings support the theory that in patients with psychopathology, dysfunction of basal ganglia-thalamo-cortical pathways could extend to limbic loops (Alexander et al., 1990; Cavallaro et al., 2002; Gündel et al., 2003; Ron, 2009; Stefurak et al., 2003). Nevertheless, further studies focusing on


37

structural and functional abnormalities between FDM patients with and without psychopathology are needed. Concluding, and in line with previous findings from our laboratory (Altenmüller & Jabusch, 2009; Enders et al., 2011; Jabusch & Altenmüller, 2004; Jabusch et al., 2004b), the results of the current thesis provide support for psychopathology constituting an aggravating risk factor in the development of FDM.

FUTURE ASPECTS

Based on the knowledge derived from the current thesis, new and related research questions and directions arise:

• Apart from psychological features related to anxiety, stress and perfectionism among FDM patients, further comorbidities related to OCD and depression remain to be examined.

• Neuroimaging studies focusing on the structural and functional brain differences

between FDM patients with and without psychopathology may provide further insights about the pathophysiology of focal dystonia.

• Intervention studies based on the application of specific treatment approaches for

FDM patients with and without psychopathology may be informative about the pathophysiology, and aid the development of new, more efficient treatments in the field of focal dystonia.

DEFINITION

Finally, an additional suggestion concerns the classification and the definition of FDM. Until now, and based on the traditional three-axis classification of dystonia: i) aetiology, ii) age at onset and iii) body distribution (Albanese et al., 2011; Fahn, 2011), FDM has been classified as primary (aetiology) and focal (body distribution). The age at onset is almost never reported as the disorder always develops in adulthood (i.e. it is a late onset dystonia). Combining the findings of the current investigation with the recently updated classification system of dystonia introduced by Albanese et al. (2013), a new classification and definition of FDM is essential. The system of Albanese et al. (2013) categorises dystonic conditions along two, instead of three main axes: i) the clinical features and ii) the aetiology. The first axis is further divided into five subgroups: i) age at onset, ii) body distribution, iii) temporal pattern, iv) associated features and v) occurrence of other neurological manifestation. The fourth subgroup is further broken down into isolated dystonia (when dystonic features are the only


38

symptoms) and combined dystonia (when dystonic features occur alongside other movement disorders such as myoclonus and parkinsonism). The word “isolated” was mainly introduced to replace the term “primary”, which Albanese et al. (2013) deemed ambiguous. The fifth subcategory (occurrence of other neurological manifestations) was included to cover the existence of additional mainly non-motor (i.e. cognitive, psychological or psychiatric) features. Therefore, according to the above classification and to the findings of the current thesis we suggest that the following definition, partly based on the general dystonia definition, (see section 1.2), would be most appropriate for FDM:

“Focal dystonia in musicians (FDM) is an isolated movement disorder characterised by sustained or intermittent muscle contractions causing abnormal postures of the affected limb

or embouchure (focal). Symptoms are often initiated or worsened by voluntary actions related to the playing of a musical instrument. FDM may occur with or without additional

non-motor neuropsychological conditions”.

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AFFIDAVIT

I herewith declare that I autonomously carried out the PhD thesis entitled “Neuropsycho-logical Triggering Factors in Musicians with Focal Dystonia”. No third party assistance has been used. I did not receive any assistance in return for payment by consulting agencies or any other person. No one received any kind of payment for direct or indirect assistance in correlation to the content of the submitted thesis. I conducted the project at the following institution: Institute of Music Physiology and Musicians’ Medicine, Hannover University of Music, Drama and Media. The thesis has not been submitted elsewhere for an exam, as thesis or for evaluation in a similar context. I hereby affirm the above statements to be complete and true to the best of my knowledge. 04.12.2015 Christos I. Ioannou ...................................................... ...................................................... date signature

55

ACKNOWLEDGEMENTS The current thesis would not have been possible to complete without the help and support of many other people. First, I would like to express my gratitude and warmest thanks to my main supervisor Prof. Dr. Eckart Altenmüller for the opportunity to work in his laboratory. His supportive, creative, critical and constructive supervision, always accompanied by friendliness, sensitivity and nice sense of humour were essential for the completion of the project. Thanks are also extended to my co-supervisors, Prof. Dr. Reinhard Dengler and Prof. Dr. Claudia Grothe, for their critical discussions and suggestions during our annual meetings.

A special thank you to the German Research Foundation (DFG) who funded the overall project and to the Hannover University of Music, Drama and Media for its excellent facilities, administration and continued assistance. Additional thanks also to the members (academic and staff) of the Centre for Systems Neuroscience (ZSN) for the exciting and high-quality courses, laboratory classes and scientific meetings during the PhD program.

Furthermore I would like to express my appreciation to all my collaborators in the Institute of Music Physiology and Musicians’ Medicine (IMMM) for the friendly and supportive atmosphere, their help in many different aspects during the last few years and their critical discussions and encouragement (Dr. André Lee, Dr. Floris van Vugt, Dr. Shinichi Furuya, Daniel Scholz, Martin Neubauer, Yousreya Pölkner, Dr. Erwin Schoonderwaldt, Dr. Felicia Pei-Hsin Cheng and Dr. Maria C. van der Steen). A special thanks also to Dr. Michael Großbach for his technical support, assistance, and critical and beneficial statistical discussions. Finally, my great appreciation and thanks to all the internship students who occasionally contributed to the project, to all the musicians who participated in the experiments, to my assistant Mai Tran who helped me with the organisation and the performance of the experiments, and to my great friend and colleague Alexander Billig for his beneficial feedback on the improvement of scientific English.

The project was part of a larger investigation focusing on task-specific cramps in musicians and athletes. During this project a great and continuing collaboration has been developed with the German Sport University Cologne - Institute of Psychology, and specifically with my great friends and colleagues Dr. Martin Klämpfl, and with Dr. Babett Helen Lobinger and Prof. Markus Raab, who I would like to thank whole-heartedly for their critical feedback and encouragement.

Furthermore, I would like to express my great thanks to all my friends but especially to Spiros Pisinos for his great support and encouragement since the very beginning of my studies. He has always stood by my side. Likewise, I would like to express my gratitude to my partner Katerina Papachristou for her patience, love and support during the last few years.

Finally, my truly appreciation and deep thanks to my family: my mother Xenia and my father Yiannis for their unconditional love, support, encouragement and trust, as well as my two brothers Charis and Kyriacos with their wives Evdokia and Lilia respectively, for their love, support, trust, critical discussions and encouragement during this magnificent academic and life journey. Σας ευχαριστώ από τα βάθη της ψυχής µου!

Doctor of Philosophy (PhD) thesis submitted

by Christos I. Ioannou

Hannover, Germany, 2015

Neuropsychological Triggering Factors in Musicians with Focal Dystonia

University of Veterinary Medicine Hannover http://www.tiho-hannover.de/de/startseite/

Centre for Systems Neuroscience

http://www.tiho-hannover.de/forschung/zsn-hannover/

Institute of Music Physiology and Musicians’ Medicine http://www.immm.hmtm-hannover.de/en/home/

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