Pathophysiologie der Musikerdystonie: Neuroplastizität und klinische Genetik

Aus dem Institut für Musikphysiologie und Musikermedizin der Hochschule für Musik und Theater Hannover

(Direktor: Prof. Dr. med. E. Altenmüller)

Pathophysiologie der Musikerdystonie:

Neuroplastizität und klinische Genetik

Dissertation zur Erlangung des Doktorgrades der Medizin in der Medizinischen Hochschule Hannover

vorgelegt von

Alexander Schmidt aus Kiel

Hannover 2008

Präsident: Prof. Dr. med. D. Bitter-Suermann

Betreuer der Arbeit: Prof. Dr. med. E. Altenmüller

Referent: Prof. Dr. med. C. Fahlke

Koreferent: PD Dr. med. K. Krampfl

Tag der mündlichen Prüfung: 05.02.09

Promotionsausschussmitglieder: Prof. Dr. S. Lenzen Prof. Dr. E. Ponimaskin Prof. Dr. R. Schwinzer

vom Senat der Medizinischen Hochschule

Hannover angenommen am: 05.02.09

mit Genehmigung der Medizinischen

Hochschule Hannover gedruckt am: 09.03.09

Inhaltsverzeichnis

1. Publikationen

1.1 Jabusch HC, Zschucke D, Schmidt A, Schüle S, Altenmüller E. Focal dystonia in musicians: treatment strategies and long-term outcome in 144 patients. Mov Disord.

2005;20(12):1623-1626. (Journal Impact Factor: 2,83)

1.2 Ragert P, Schmidt A, Altenmüller E, Dinse HR. Superior tactile performance and learning in professional pianists: evidence for meta-plasticity in musicians. Eur J Neurosci. 2004;19(2):473-478. (Journal Impact Factor: 3,82)

1.3 Schmidt A, Jabusch HC, Altenmüller E, Hagenah J, Brüggemann N, Hedrich K, Saunders-Pullman R, Bressman SB, Kramer PL, Klein C. Dominantly transmitted focal dystonia in families of patients with musician’s cramp. Neurology 2006;67(4):691-693. (Journal Impact Factor: 5,69)

1.4 Schmidt A, Jabusch HC, Hagenah J, Enders L, Brüggemann N, Lohmann K, Saunders-Pullman R, Bressman SB, Kramer PL, Münchau A, Altenmüller E, Klein C.

Clinical genetics of musician's dystonia. Mov Disord. 2007;22(Suppl. 16):S116.

(Journal Impact Factor: 3,32)

2. Zusammenfassung

2.1 Einleitung

2.2 Ergebnisse und Diskussion 2.3 Auszeichnungen und Förderung 2.4 Referenzen

2.5 Zusammenfassung

3. Lebenslauf

4. Danksagung

5. Erklärung

Focal Dystonia in Musicians:

Treatment Strategies and Long- Term Outcome in 144 Patients

Hans-Christian Jabusch, MD,¹

Dorothea Zschucke, MD,¹Alexander Schmidt,¹ Stephan Schuele, MD, MPH,²

and Eckart Altenmu¨ller, MD¹*

1Institute of Music Physiology and Musicians’ Medicine, University of Music and Drama, Hannover, Germany;

2Department of Neurology and Medical Center for Performing Artists, Cleveland Clinic Foundation, Cleveland,

Ohio, USA

Abstract:We present the long-term outcome of 144 musi- cians with focal dystonia after treatment with botulinum toxin (nⴝ 71), trihexyphenidyl (nⴝ 69), pedagogical re- training (nⴝ24), ergonomic changes (nⴝ51), or nonspe- cific exercises on the instrument (nⴝ 78). Outcome was assessed by patients’ subjective rating of cumulative treat- ment response and response to individual therapies.

Seventy-seven patients (54%) reported an alleviation of symptoms: 33% of the patients with trihexyphenidyl, 49%

with botulinum toxin, 50% with pedagogical retraining, 56% with unmonitored technical exercises, and 63% with ergonomic changes.© 2005 Movement Disorder Society

Key words: dystonia; musician; botulinum toxin; trihexy- phenidyl; ergonomic changes; retraining

Focal task-specific dystonia in musicians presents as a loss of voluntary motor control of extensively trained movements while playing the instrument.^{1– 4}Focal dys- tonia is highly disabling and in many cases terminates the musical career. Approximately 1% of all musicians are affected.⁴ Therapeutic options include anticholin- ergic medication with trihexiphenidyl, botulinum toxin (BT) injections, retraining, and ergonomic modifica- tions.^{4 –9} Information on treatment selection, treatment response, and long-term outcome is limited.

PATIENTS AND METHODS

One hundred sixty consecutive professional musicians and music students with musician’s dystonia were re- cruited for a survey of treatment results. All patients

were seen between 1994 and 2001 at the Institute of Music Physiology and Musicians’ Medicine, Hannover University of Music and Drama. The patients underwent a complete neurological examination to exclude second- ary dystonias and were observed while playing their instruments. Therapeutic approaches, as monotherapies or in simultaneous or successive combination, included the following options.

Trihexyphenidyl was offered as first-line medical treatment in patients without contraindication. BT injec- tions were recommended to patients in whom primary dystonic movements could be clearly distinguished from secondary compensatory movements. Target muscles were identified by visual inspection of the dystonic movement patterns while patients were playing their instruments. A lyophilized botulinum toxin A powder (Dysport, Ipsen, Berkshire, U.K.) was injected using an EMG-guided technique.

Pedagogical retraining was offered to patients with all forms of musician’s dystonia. This comprised a variety of supervised behavioral approaches that included ele- ments based on the following principles reported previ- ously^7–9: affected body parts were limited to a level of tempo and force at which the dystonic movement would not occur; compensatory movements (e.g., of adjacent fingers) were avoided, partially under the application of splints; instant visual feedback with mirrors or monitors helped patients to recognize dystonic and nondystonic movements; and body awareness techniques (e.g., Fel- denkrais) were applied to increase the patient’s percep- tion of nondystonic movements.

Ergonomic changes were recommended whenever ap- plicable. The aim of ergonomic changes was blocking of dystonic movements, e.g., by attaching splints to the affected fingers. Alternatively, circumvention of dys- tonic movements was achieved by modifications to the instrument, e.g., the repositioning of individual keys in woodwind instruments or the replacement of ring keys with plateau keys.⁴ Support systems (belts, stands, tri- pods) were recommended when the dystonic hand had to carry the instrument while playing. Besides the afore- mentioned inclusion/exclusion criteria, the choice of treatment was strongly influenced by patient preference.

A retrospective chart review was performed, and out- come data were assessed using a standardized question- naire. Patients were asked to estimate the cumulative treatment response on a four-step scale (free of symp- toms; improved; no change; deteriorated) and the treat- ment response to individual therapies (improvement; no effect; deterioration). They were asked about the nature and duration of therapies not applied by the authors (e.g., nonspecific exercises on the instrument) and their musi-

*Correspondence to: Dr. Eckart Altenmu¨ller, Institute of Music Physiology and Musicians’ Medicine, University of Music and Drama, Hohenzollernstrasse 47, 30161 Hannover, Germany.

E-mail: altenmueller@hmt-hannover.de

Received 8 April 2004; Revised 2 February 2005; Accepted 8 March 2005

Published online 2 August 2005 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/mds.20631

MUSICIAN’S DYSTONIA 1623

Movement Disorders, Vol. 20, No. 12, 2005

Superior tactile performance and learning in professional pianists: evidence for meta-plasticity in musicians

Patrick Ragert,^1,2Alexander Schmidt,³ Eckart AltenmuÈller³andHubert R. Dinse¹

1Institute for Neuroinformatics, Theoretical Biology Ruhr-University, D-44780Bochum, Germany

2International Graduate School of Neuroscience (IGSN), Ruhr-University, D-44780Bochum, Germany

3Institute of Music Physiology and Musicians' Medicine, University for Music and Theatre, D-30175 Hanover, Germany

Keywords: Hebbian learning, humans, musicians, perceptual learning, plasticity, tactile

Abstract

Musician's brains constitute an interesting model for neuroplasticity. Imaging studies demonstrated that sensorimotor cortical representations are altered in musicians, which was assumed to arise from the development of skilled performance. However, the perceptual consequences of the cortical changes remain elusive. Here we ask whether cortical reorganization induced by professional musical skill training is paralleled by the evolution of other, unrelated perceptual abilities. We therefore studied psychophysically tactile spatial acuity as an indirect marker of cortical changes in professional pianists and non-musician control subjects using a simultaneous two-point discrimination paradigm. We show that long-lasting piano practising resulted in lower spatial discrimination thresholds in comparison to non-musicians. In musicians, individual discrimination thresholds were linearly correlated with the daily training duration, indicating a direct link between tactile acuity and the degree of piano practising. To investigate whether the superior acuity in pianists is subject to further improvement, we used a Hebbian stimulation protocol of tactile coactivation known to improve spatial tactile acuity.

Three hours of coactivation further reduced their discrimination thresholds. The coactivation-induced gain in pianists was signi®cantly larger in comparison to control subjects and correlated with the years of heavy daily practising (>3 h/day), but not with the total years including casual playing. Our results suggest that despite already high-level performance in pianists, Hebbian learning was more effective in musicians than in controls. This implies stronger capacities for plastic reorganization and points to enhanced learning abilities implicating a form of meta-plasticity in professional pianists.

Introduction

Many lines of evidence suggest that alterations of afferent input statistics resulting from altered use, stimulation and practise play a crucial role for the induction of cortical plasticity (Merzenichet al., 1988; Elbertet al., 1997; Recanzone, 2000; Dinse & Merzenich, 2002;

Kilgardet al., 2002). In fact, imaging studies showed that continuous and long-lasting practise of sensorimotor skills, which is paralleled by an intensi®cation of sensory inputs, resulted in de®ned expansions of cortical representational areas, as described for blind Braille readers and musicians (Pascual-Leoneet al., 1993; Elbertet al., 1995; Pantev et al., 1998; Sterr et al., 1998; Rauschecker, 2001). Recently, grey matter differences between pianists and non-musicians extending from the premotor region to the primary somatosensory cortex and into the anterior parietal lobe have been described (Gaser & Schlaug, 2003).

In contrast, studies in humans (Liepert et al., 1995) and animals (D'Amelio et al., 1996; JuÈrgens & Dinse, 1997; Coq & Xerri, 1999) provided clear evidence that reduced use, and thus altered and reduced input statistics, cause a reduction of cortical representa- tional areas. In addition, many studies have demonstrated that plastic cortical changes can be evoked by variation of input statistics alone without involving cognitive or attentional mechanisms, provided the statistics are suf®ciently altered (Diamondet al., 1993; Wanget al.,

1995; Goddeet al., 1996, 2000; Liepertet al., 1999; Plegeret al., 2001;

Watanabeet al., 2001; Dinse & BoÈhmer, 2002; Dinse & Merzenich, 2002; Dinseet al., 2003a,b).

While MEG and EEG studies demonstrated that musicians have altered cortical representations (Elbertet al., 1995; Pantevet al., 1998;

MuÈnteet al., 2001; Rauschecker, 2001; Schlaug, 2001; for review, see MuÈnteet al., 2002), the speci®city of these reorganizational changes remains to be clari®ed. In our view, there are two possibilities. These changes are highly speci®c in the sense that they allow for improve- ment of the trained motor or perceptual skill only, i.e. the neural changes arising from skill training are assumed to have little con- sequences for information processing beyond that skill. In an alter- native scenario, that we believe might be more appropriate, neural changes result in a widespread modi®cation of the entire sensory processing. In this case, extensive consequences in terms of perceptual and behavioural abilities are to be expected that must generalize widely beyond the trained skill. In other words, is a training-induced improvement paralleled by other perceptual changes, either positive or negative, that are manifested independently from the trained perfor- mance?

Here we show that skill-induced behavioural improvement as found in professional pianists is paralleled by other perceptual changes not directly related to the speci®c demands of piano playing. We provide psychophysical evidence that pianistic skills are accompanied by the development of additional perceptual abilities that appear to be based on an enhancement of speci®c learning capabilities.

European Journal of Neuroscience, Vol. 19, pp. 473±478, 2004 ßFederation of European Neuroscience Societies

doi:10.1111/j.1460-9568.2003.03142.x

Correspondence: P. Ragert,¹Institute for Neuroinformatics, as above.

E-mail: patrick.ragert@neuroinformatik.ruhr-uni-bochum.de

Received 27 August 2003, revised 5 November 2003, accepted 17 November 2003

DOI: 10.1212/01.wnl.0000230148.00035.f9 2006;67;691-693

Neurology

R. Saunders-Pullman, S. B. Bressman, P. L. Kramer and C. Klein

A. Schmidt, H. -C. Jabusch, E. Altenmüller, J. Hagenah, N. Brüggemann, K. Hedrich, cramp

Dominantly transmitted focal dystonia in families of patients with musician’s

This information is current as of November 23, 2006

http://www.neurology.org/cgi/content/full/67/4/691 located on the World Wide Web at:

The online version of this article, along with updated information and services, is

Print ISSN: 0028-3878. Online ISSN: 1526-632X.

published continuously since 1951. Copyright © 2006 by AAN Enterprises, Inc. All rights reserved.

Neurology is the official journal of AAN Enterprises, Inc. A bi-monthly publication, it has been

by CHRISTINE KLEIN on November 23, 2006 www.neurology.org

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Clinical genetics of musician’s dystonia

Schmidt A¹, Jabusch HC¹, Hagenah J², Enders L¹, Brüggemann N², Lohmann K^2,3, Saunders-Pullman R^4,5, Bressman SB^4,5, Kramer PL⁶, Münchau A⁷, Altenmüller E¹, Klein C^2,3

1Institute of Music Physiology and Musicians’ Medicine, Hannover University of Music and Drama; ²Departments of Neurology and ³Human Genetics, Lübeck University;

Departments of Neurology at: ⁴Beth Israel Medical Center, New York; ⁵Albert Einstein College of Medicine, New York;

6Oregon Health & Sciences University, Portland; ⁷University Medical Center Hamburg-Eppendorf Correspondence: christine.klein@neuro.uni-luebeck.de schmidt-alexander@gmx.net

Background

Patients and Methods

Results

Conclusions

References

Musician’s dystonia (MD), a type of focal task-specific dystonia (FTSD), presents with loss of voluntary motor control of highly trained movements (Fig. 1).

It is generally considered a sporadic disorder.¹A genetic contribution has recently been suggested.²

The families of 28 index patients suffering from MD (14 with a reported positive family history (FH+) of FTSD and 14 with no known family history (FH?)) underwent a standardized telephone screening interview using the Beth Israel Dystonia Screen (BIDS; adapted from Saunders-Pullman et al.³).

Pedigrees of all families were constructed (example: see Fig. 2).

Videotaped neurological examinations were performed in:

• all 28 index patients,

• all relatives with a known or reported form of FTSD,

• all relatives with previously not known movement disorders who screened positive for dystonia using the BIDS.

The videotapes were independently reviewed by three neurologists and consensus diagnoses were established. A diagnosis of dystonia was made following previously published criteria:^1,4

• Definite (def): muscle contractions producing characteristic twisting or flexion or extension movements and postures consistently present.

• Probable (prob): movements and postures of insufficient intensity or consistency to merit classification as definite.

• Possible (poss): muscle contractions not considered abnormal but remotely suggestive of dystonia.

1. Altenmüller E. Focal dystonia: advances in brain imaging and understanding of fine motor control in musicians. HandClin 2003; 19:523–538.

2. Schmidt A, Jabusch HC, Altenmüller E, Hagenah J, Brüggemann N, Hedrich K, Saunders-Pullman R, Bressman SB, Kramer PL, Klein C. Dominantly transmitted focal dystonia in families of patients with musician’s cramp. Neurology 2006; 67(4):

691-693.

3. Saunders-Pullman R, Soto-Valencia J, Costan-Toth C, Shriberg J, Raymond D, Derby CA, Lipton RB, Bressman SB. A new screening tool for cervical dystonia.

Neurology 2005; 64:2046–2049.

4. Bressman SB, Raymond D, Wendt K, Saunders-Pullman R, De Leon D, Fahn S, Ozelius L, Risch N. Diagnostic criteria for dystonia in DYT1 families. Neurology 2002;59:1780-1782.

Besides the 28 index patients, 15 relatives directly reported a form of FTSD. FTSD was additionally reported in 2 deceased relatives (MD: n = 1, WC: n = 1).

BIDS screening of another 78 family members identified an additional 11 possibly affected individuals.

MD was established by personal examination and videotape review in all 28 index patients (def: n = 27; prob: n = 1) With the same procedure, a type of dystonia was confirmed (def or prob) in 19/26 of the putatively affected relatives, 5 of whom were members of FH? families (MD: n = 8, other FTSD:

n = 9, other dystonias: n = 2).

Our results suggest a genetic contribution to FTSD with phenotypic variability including MD.

Patients with MD may display additional types of FTSD, other focal and non-focal types of dystonia and/or other movement disorders.

Hypo- and hyperkinetic movement disorders are present in a considerable number of relatives of index patients with MD.

Grant monies

This work was supported by the Dystonia Medical Research Foundation, the Bachmann-Strauss Dystonia & Parkinson’s Foundation, Inc., and the Volkswagen Foundation.

Figure 1: Pianist with MD.

All patients were investigated for the presence of the GAG deletion in DYT1and suitable families were tested for linkage to DYT7 locus.

Details of methods and results are given in Fig.3.

Figure 2: Pedigree of a family with a positive family history of FTSD. Asterisks (*) indicate videotaped and personally examined patients. Family members interviewed with the BIDS are marked with a pound sign (#). Symbols of definitely affected family members are shaded in black; symbols of possibly affected family members are shaded in gray; the index patient is marked with an arrow; deceased individuals are slashed. →See video demonstration.

In 27 of the 47 definitely/probably affected individuals, signs for one (n = 18), two (n = 8) or three (n = 3) additional forms of dystonia were seen, other movement disorders were observed in 23 patients.

Review of videotaped examinations in a total of 53 individuals revealed evidence for the following other movement disorders (def/prob):

• mirror movements (n = 9) • dyskinesia (n = 2)

• tremor (n = 7) • parkinsonism (n = 2)

• tic (n = 4) • perioral extra movements (n = 2)

• chorea (n = 3) • athetosis (n = 1)

• reduced arm swing (n = 3)

In total, 18 families were multiplex families (based on def/prob/poss diagnoses of dystonia) with 2-4 affected members (see Fig. 4) in one (n = 6), two (n = 10) or three (n = 2) generations, compatible with autosomal dominant inheritance in at least 12 families.

The DYT1mutation was not present in any of the tested patients. Linkage to the DYT7locus could not be excluded in any of the 11 informative small families.

Figure 3: Flow chart displaying progress and results of the study. FH: family history; FH+: reported positive family history of FTSD; FH?: no known family history; pts.: patients;

MD: musician’s dystonia; FTSD: focal task-specific dystonia; BIDS: Beth Israel Dystonia Screen.; def: definite; prob: probable; poss: possible; (+): additional dystonias and/or other movement disorders present in some individuals.

Previously known history

Family history interview

BIDS

Videotaped examination

+ blinded video rating

def/

prob dystonia def/prob/

poss dystonia

FH

based on def/prob def/prob/poss

diagnoses Information

based on: 14 index pts. MD 56 relatives

17 relatives FTSD/MD (2 deceased)

38 putatively unaffected

relatives

1 relative MD (deceased)

34 relatives screened negative 4 relatives

screened positive

14 MD(+)

14 MD(+)

7 MD(+), 6 other FTSD(+), 1 other type of dystonia(+) 10 MD(+), 10 other FTSD(+),

1 other type of dystonia(+)

10 families FH+

13 families FH+

14 families FH+

14 index pts. MD 41 relatives

1 relative MD (deceased)

33 relatives screened

negative 7 relatives

screened positive

14 MD(+)

14 MD(+)

1 MD(+), 3 other FTSD(+), 1 other type of dystonia(+) 2 MD(+), 4 other FTSD(+), 1 other type of dystonia(+)

3 families FH+

5 families FH+

14 families FH?

Genetic analyses

GAG deletion in DYT1: not present in any patient

DYT7locus: Linkage could not be excluded in any of the 11 informative small families

Figure 4:Number of family members affected with dystonia in the 14 families with a reported family history of FTSD (FH+) and in the 14 families with no known family history (FH?).

Blue bars: number of family members with previously known FTSD.

Red bars: number of family members definitely or probably affected with dystonia (according to video rating).

Yellow bars: number of family members definitely, probably or possibly affected with dystonia.

The aim of this study was to investigate a potential role of genetic factors in MD.

2. Zusammenfassung

2.1 Einleitung

Die Dystonie ist eine neurologische Bewegungsstörung und gehört zur Gruppe der extrapyramidalmotorischen Erkrankungen. Eine mögliche Einteilung orientiert sich an der Symptomverteilung. Es werden fokale Dystonien, die an einem umschriebenen Ort (z. B. der Hand) auftreten, von generalisierten Dystonien abgegrenzt.

Die Fokale Dystonie des Musikers gehört zu den fokalen tätigkeitsspezifischen Dystonien und ist durch den Verlust der feinmotorischen Kontrolle am Instrument charakterisiert. Jahrzehntelang geübte zeitlich und räumlich hochpräzise Instrumentalbewegungen können von betroffenen Musikern nicht mehr korrekt ausgeführt werden. Koordinationsstörungen und unwillkürliche Muskelkontraktionen während des Instrumentalspiels können die obere Extremität als Handdystonie sowie die orofaziale Muskulatur bei Bläsern als Ansatzdystonie betreffen.

Epidemiologische Studien zeigen, dass ca. 1 % aller Musiker von einer Musikerdystonie betroffen sind.

Die Bewegungsstörung führt zu einer erheblichen Beeinflussung des Berufslebens. Eine große Zahl von Patienten muss die musikalische Karriere beenden.

Pharmakologische Therapieoptionen der Musikerdystonie sind die intramuskuläre Injektion von Botulinumtoxin in betroffene Muskeln, sowie die orale Applikation des anticholinerg wirkenden Medikaments Trihexyphenidyl. Als nichtpharmakologische Therapieoptionen stehen verschiedene Retrainingverfahren zur Verfügung, mit deren Hilfe die korrekte Wiederherstellung von dedifferenzierten Repräsentationsarealen der rezeptiven Felder im somatosensorischen System erreicht werden soll. Ferner werden ergonomische Veränderungen an Instrumenten vorgenommen.

Die Pathophysiologie der Musikerdystonie ist heterogen und nicht restlos aufgeklärt.

Neurophysiologische Untersuchungen deuten auf einen Mangel an lateraler Inhibition zentraler

motorischer Efferenzen hin. Die mangelhafte Hemmung ist vor allem im Bereich der

Basalganglien, aber auch auf anderen Ebenen des zentralen Nervensystems lokalisiert.

Auch das

somatosensorische System ist bei der Musikerdystonie betroffen. Als Folge einer Überstimulation

2.5 Zusammenfassung

Die Musikerdystonie gehört zu den fokalen tätigkeitsspezifischen Dystonien und ist durch den Verlust der feinmotorischen Kontrolle am Instrument charakterisiert.

Die vorliegende Arbeit beinhaltet drei zusammenhängende Projekte zur Musikerdystonie, von denen eines thematisch zu Therapieoptionen und –ergebnissen bei Musikerdystoniepatienten gehört. Die zwei weiteren Projekte sollen zum Verständnis der bisher nicht restlos geklärten Pathophysiologie der Musikerdystonie beitragen, wobei das Projekt zur Erforschung der genetischen Komponente bei der Entstehung der Musikerdystonie den Schwerpunkt bildet.

Hauptergebnis des Therapieprojekts ist, dass dank der heute verfügbaren therapeutischen Optionen einem Großteil der Patienten mit Musikerdystonie geholfen werden kann. Die Ergebnisse für Patienten mit Ansatzdystonien dokumentieren die Notwendigkeit zur Entwicklung neuer Therapieansätze bzw. die Notwendigkeit zur Prävention der Musikerdystonie.

Die Projekte zur Pathophysiologie der Musikerdystonie zeigen, dass der Neuroplastizität eine zentrale Bedeutung beim Erlernen und Beherrschen eines Musikinstruments zukommt.

Maladaptive Vorgänge können dabei zur Entstehung der Musikerdystonie beitragen. Ferner weisen die Ergebnisse des Neurogenetikprojekts auf eine hereditäre Komponente bei der Entstehung fokaler tätigkeitsspezifischer Dystonien hin, mit unterschiedlicher phänotypischer Ausprägung einschließlich der Musikerdystonie.

Daraus ergibt sich als langfristiges Ziel das für die Musikerdystonie verantwortliche Gen zu

identifizieren, um betroffenen Patienten präventiv und therapeutisch noch besser helfen zu

können.

3. Lebenslauf

Persönliche Daten

Name: Alexander Schmidt Geburt: 15.01.1977 in Kiel

Familie: erstes von fünf Kindern des

Mathematikprofessors Dr. Roland Schmidt und der Grund- und Hauptschullehrerin Edeltraut Schmidt (geb. Gottlebe)

Familienstand: seit 2002 verheiratet mit der Konzertpianistin und Klavierpädagogin Saskia Maria Schmidt-Enders (geb. Enders)

2003 Geburt des Sohnes Victor Maria Schmidt 2006 Geburt des Sohnes Gero Leander Schmidt

Schulbildung und musikalische Ausbildung

1983-1987 Besuch der Brüder-Grimm-Schule in Kronshagen

1987-1996 Schüler im künstlerischen Zweig des Ernst-Barlach Gymnasiums in Kiel (Abitur: Durchschnittsnote 1,3)

1991-1996 zahlreiche erste Preise beim Wettbewerb „Jugend musiziert“ im Fach Soloklavier und Klavierbegleitung (auch auf Bundesebene) sowie Konzerttätigkeit mit Klavier und Violine im In- und Ausland in unterschiedlichen Besetzungen

1993-1996 Stipendium zur Förderung künstlerischer Begabungen der Heimatgemeinde

Zivildienst

1996-1997 im Rudolf-Steiner-Kindergarten für schwer erziehbare und behinderte Kinder in Kiel

Musikstudium

1997-2001 Klavierstudium bei Prof. W. Krajnew (Schüler von Heinrich Neuhaus) mit Nebenfach Violine im Studiengang Musikerziehung an der

Hochschule für Musik und Theater Hannover

zahlreiche Klavierkonzerte im In- und Ausland solistisch und im Ensemble

Preise bei nationalen und internationalen Klavierwettbewerben 2000-2002 Lehrtätigkeit im Fach Klavier

2001 Diplomprüfung im Studiengang Musikerziehung Studienrichtung Instrumentallehrer (Gesamtnote -sehr gut-)

Diplomarbeit: „Untersuchungen zur Fingerfeinwahrnehmung bei

Pianisten“ bei Prof. Dr. med. E. Altenmüller am Institut für

Musikphysiologie und Musikermedizin (IMMM) in Hannover

4. Danksagung

Mein erster und ganz besonderer Dank gilt dem Betreuer dieser Dissertation Prof. Dr. med. E.

Altenmüller für seine jahrelange uneingeschränkte Unterstützung und Förderung meines beruflichen Werdeganges und meiner persönlichen Entwicklung in seinem Institut.

Für die großartige, fachlich überaus lehrreiche und darüber hinaus sehr menschliche Betreuung meiner Arbeit möchte ich Prof. Dr. med. H.-C. Jabusch meinen Dank aussprechen.

Ganz herzlich danke ich Frau Prof. Dr. med. C. Klein für das große Vertrauen in meine Person und Arbeit und für die außergewöhnliche Motivation und Förderung.

Ein besonderer Dank gilt natürlich auch meiner gesamten Familie, insbesondere meinen beiden Kindern Victor und Gero, meinen Eltern und Schwiegereltern.

Danken und widmen möchte ich die Dissertation meiner lieben Frau Saskia.

5. Erklärung

Ich erkläre, dass ich die der Medizinischen Hochschule Hannover zur Promotion eingereichte Dissertation mit dem Titel „Pathophysiologie der Musikerdystonie: Neuroplastizität und klinische Genetik“ im Institut für Musikphysiologie und Musikermedizin unter Betreuung von Prof. Dr. med. E. Altenmüller ohne sonstige Hilfe durchgeführt und bei der Abfassung der Dissertation keine anderen als die dort aufgeführten Hilfsmittel benutzt habe.

Ich habe die Dissertation bisher an keiner in- oder ausländischen Hochschule zur Promotion eingereicht. Weiterhin versichere ich, dass ich den beantragten Titel bisher noch nicht erworben habe.

Hannover, den 15.04.08

cal activity and professional situation today. Data were analyzed using␹²tests for outcome measures and mul- tiple regression analyses for predictability of treatment responses. Percentage rates were calculated based on the total number of available answers.

RESULTS

Outcome data from 144 patients (116 men, 28 women) were available. The mean age at onset of symptoms was 33 years; the mean age at the time of the survey was 42 years. Mean duration of dystonic symptoms at the time of the first visit was 5.1 years. Outcome was revealed on average 8.4 years after onset of dystonic symptoms and 3.4 years after the initial visit. At onset, 74 patients (51%) had professional positions as soloists, 24 (17%) were tutti players in orchestras, 25 patients (17%) were teachers, and 21 (15%) were students. Twenty-two pa- tients (15%) were bowed string players, 40 patients (28%) were keyboard instrumentalists, 29 patients (20%) played plucked instruments, 37 patients (26%) were woodwind players, and 16 patients (11%) were brass players. One hundred twenty-four patients had upper limb dystonias (86%) and 20 patients (14%) embouchure dystonias.

At the time of the survey, 2 patients (1%) were free of symptoms, 75 patients (52%) reported an improvement of symptoms as compared to the time of their first visit, 50 patients (35%) did not notice any changes, and 16 patients (11%) reported a deterioration. A change of profession was reported by 35 patients (29%), predomi- nantly among music students (57%).

Dystonic symptoms were present in other everyday activities (handwriting, computer keyboard) in 49 pa- tients (34%) at the time of the first visit and in 68 patients (47%) at the time of the survey. In five patients (3%), symptoms initially occurred in nonmusical activities and later spread to instrumental playing. Regardless of treat- ment, a smaller fraction of patients with embouchure

dystonia showed an improvement (3 of 20 patients) com- pared to those with limb dystonia (62 of 123 patients;␹²

⫽8.7; df⫽ 1;P⬍0.01).

Specific Treatment Effects

Trihexyphenidyl was applied in 69 patients (48% of all) with an average maximum dosage of 11 mg/day (range, 1–30). Within 2 months, the medication was interrupted in 20 patients due to side effects or unsatis- fying treatment response. The other 49 patients (34% of all) received trihexyphenidyl on average 16 months (range, 3– 67). Most frequent side effects were dry mouth, fatigue, dizziness, agitation, memory impairment, drowsiness, depression, loss of concentration, nausea, hyperkinesia, impaired visual accommodation, tremor (42% to 3%, in decreasing order of frequency). Side effects were not dependent on age or gender. The aver- age minimum dosage at which side effects occurred was 9 mg/day (range, 1–20). In 16 patients (23%), trihexy- phenidyl was stopped due to side effects. Improvement with trihexyphenidyl was reported by a total of 23 pa- tients (33%) with limb dystonia, among them 19 patients who received trihexyphenidyl for more than 2 months (42% of these; average duration, 26 months). Patients’

rating of specific treatment results is displayed in Figure 1. None of five patients with embouchure dystonia re- ported an improvement. No correlation was seen be- tween side effects and improvement rate. Average max- imum dosage was 11 mg/day (range, 4 –30) in patients who had an improvement and 11 mg/day (range, 1–20) in patients with no improvement. Multiple regression anal- ysis revealed the following variables as predictors of a positive rating of trihexyphenidyl effects (r²adjusted⫽ 0.49): limb localization of dystonia (vs. embouchure dystonia:␤ ⫽0.59; df⫽1; F⫽37;P⬍0.001), a high maximum dosage (␤ ⫽0.28; df⫽1; F⫽6.8;P⫽0.01), a low number of concomitant treatments (␤ ⫽ ⫺0.35;

df⫽ 1; F⫽ 11;P ⬍0.01). The variables age, gender,

FIG. 1. Patients’ rating of treatment re- sults. Black bars, deterioration of dys- tonic symptoms; gray bars, no change of dystonic symptoms; white bars, allevia- tion of dystonic symptoms; hatched bars, no answer. Results are given separately for all patients who received trihexy- phenidyl (Trhx) vs. those who received Trhx for more than 2 months. Results are given separately for all patients who re- ceived BT vs. those who received more than one injection.

1624 H.-C. JABUSCH ET AL.

Movement Disorders, Vol. 20, No. 12, 2005

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VIDEO

Dominantly transmitted focal dystonia in families of patients with musician’s cramp

Abstract—Musician’s dystonia is generally considered a sporadic disorder. We present three families with the index patient affected by musician’s dystonia, but other forms of upper limb focal task–specific dystonia (FTSD), mainly writer’s cramp, in seven relatives. Our results suggest a genetic contribution to FTSD with phenotypic variability, including musician’s dystonia.

NEUROLOGY 2006;67:691–693

A. Schmidt, MA; H.-C. Jabusch, MD; E. Altenmu¨ller, MD, MA; J. Hagenah, MD; N. Bru¨ggemann, MD;

K. Hedrich, PhD; R. Saunders-Pullman, MD, MPH; S.B. Bressman, MD; P.L. Kramer, PhD;

and C. Klein, MD

No genetic cause of musician’s dystonia, a type of focal task–specific dystonia (FTSD),^1,2 has been mapped or identified, and little is known about the genetics of other forms of focal dystonia that repre- sent the most common form of dystonia. Clinical ex- amination of relatives of patients with focal dystonia revealed affected family members in approximately 25%.³ The epidemiology of musician’s dystonia sug- gests a possible genetic component also in this type of dystonia: 10% of musicians with dystonia report a positive family history of dystonia.¹ In rare cases, a hereditary component has been demonstrated in pa- tients with focal dystonia, such as the GAG deletion in the DYT1 gene.⁴ However, this mutation was ex- cluded in a small group of musicians with dystonia.⁵ In one family, focal dystonia has been linked to a specific gene locus (DYT7).⁶We describe three multi- plex families with musician’s dystonia and other forms of FTSD.

Methods. We conducted a pilot study on three families identi- fied through three index patients with musician’s dystonia fol- lowed at the outpatient clinic of the Institute of Music Physiology and Musicians’ Medicine with a reported (Families A and B) or suspected (Family C) family history of FTSD. The families origi-

nated from different geographic regions in Germany (Families A and B) and the Ukraine/Russia (Family C). After approval of the study by the local ethics committee, the index patients were ini- tially contacted by letter, followed by a telephone call. After ob- taining written informed consent, pedigrees of the families were constructed. All family members with known or reported dystonia willing and able to participate underwent videotaped neurologic examinations. Questionnaires covering demographic information, handedness, and medical and occupational history were adminis- tered, and a blood sample was collected. The severity of the dysto- nia was rated with the Abnormal Involuntary Movement Scale in the most severely affected limb and the Global Disability Score (table). All other available and consenting family members under- went a telephone interview including the Beth Israel Dystonia Screen (BIDS) (adapted from Saunders-Pullman et al.⁷). If screened positive, the same examinations as described for family members with known dystonia were performed. If negative, only questionnaires and blood samples were collected by mail. The videotapes were independently reviewed by four members of the team (E.A., H.-.C.J., J.H., and C.K.), and a consensus diagnosis was established. A diagnosis of dystonia was made following previously published criteria^1,8: 1) definite: muscle contractions producing characteristic twisting or flexion or extension move- ments and postures consistently present; 2) probable: move- ments and postures of insufficient intensity or consistency to merit classification as definite; 3) possible: muscle contractions not considered abnormal but remotely suggestive of dystonia; 4) no dystonia. All patients were tested for the known mutations in theDYT1gene.

Results. All three index patients with musician’s dysto- nia, a pianist and two guitarists, had two (n⫽2) or three (n⫽1) first-degree relatives identified with other forms of FTSD affecting the arms. The diagnosis of dystonia was definite in six and probable in one of the relatives. All affected family members had writer’s cramp, except one with “handicraft dystonia,” which occurred when threading a needle. A potential trigger of the dystonia (mostly in- creased practice) was reported by half of the dystonia pa- tients, including two of the three musicians. Detailed demographic, clinical, and pedigree information on all 10 patients and all examined relatives is summarized in the table and the figure. No patient reported neuroleptic expo- sure or significant peripheral trauma of the affected arm.

Mode of transmission was compatible with autosomal dominant inheritance. In Families B and C, none of the affected individuals had related their dystonia to the musi- cian’s dystonia in their family.

Patient A.II.4, the mother of the pianist A.III.1, and Patient C.III.4, the sister of the guitarist C.III.1, were also professional pianists. They had writer’s cramp but did not show any dystonic signs when playing the piano. Patient B.III.1 with guitarist’s cramp reported additional discom-

Additional material related to this article can be found on theNeurology Web site. Go to www.neurology.org and scroll down the Table of Con- tents for the August 22 issue to find the title link for this article.

From the Institute of Music Physiology and Musicians’ Medicine, Hanover University of Music and Drama, Hanover, Germany (A.S., H.-C.J., E.A.);

Departments of Neurology (J.H., N.B., K.H., C.K.) and Human Genetics (K.H., C.K.), Lu¨beck University, Lu¨beck, Germany; Department of Neurol- ogy, Beth Israel Medical Center, New York, NY (R.S.-P., S.B.B.); Depart- ment of Neurology, Albert Einstein College of Medicine, Bronx, NY (R.S.-P., S.B.B.); and Department of Neurology, Oregon Health & Sciences Univer- sity, Portland, OR (P.L.K.).

This work was supported by the Volkswagen Foundation, the Dystonia Medical Research Foundation, and the Bachmann-Strauss Dystonia & Par- kinson’s Foundation, Inc.

Disclosure: The authors report no conflicts of interest.

Received January 10, 2006. Accepted in final form April 20, 2006.

Address correspondence and reprint requests to Dr. Christine Klein, De- partment of Neurology, University of Lu¨beck, Ratzeburger Allee 160, 23538 Lu¨beck, Germany; e-mail: christine.klein@neuro.uni-luebeck.de

Copyright © 2006 by AAN Enterprises, Inc. 691

by CHRISTINE KLEIN on November 23, 2006 www.neurology.org

Downloaded from

(z. B. durch Overuse oder Nervenschädigung) kommt es durch maladaptive Neuroplastizität zur Dedifferenzierung rezeptiver Felder im somatosensorischen System.

Ferner weisen epidemiologische Daten auf eine hereditäre Komponente bei der Entstehung der Musikerdystonie hin. Bei ca. 10 % der Patienten mit Musikerdystonie sind weitere Angehörige von einer fokalen tätigkeitsspezifischen Dystonie betroffen.

Ca. 80 % der betroffenen Musiker sind männlichen Geschlechts.

Bisher konnte noch kein für die Musikerdystonie verantwortliches Gen identifiziert werden. Bei einigen Patienten mit fokaler Dystonie konnte eine GAG-Deletion im

Eine Kopplung zum

Familie, in der fokale tätigkeitsspezifische Dystonien aufgetreten waren, gefunden.

Bestandteil der vorliegenden Arbeit sind drei zusammenhängende Projekte zur Musikerdystonie, aus denen mehrere englischsprachige Publikationen entstanden. Thema des ersten Projekts ist die Therapie der Musikerdystonie, während das zweite und dritte Projekt zur Aufklärung der Pathophysiologie der Musikerdystonie beitragen sollen. Das dritte Projekt bildet den Schwerpunkt der vorliegenden Arbeit. Ziel war es, die bisher nicht identifizierte genetische Komponente bei der Entstehung der Musikerdystonie aufzudecken.

Projekt 1: zu Therapieoptionen und -ergebnissen bei Musikerdystoniepatienten Projekt 2: zur adaptiven Neuroplastizität professioneller Pianisten

Projekt 3: zur Erforschung der klinischen und molekularen Neurogenetik der Musikerdystonie

Alle Projekte wurden am Institut für Musikphysiologie und Musikermedizin in Hannover

(IMMM) unter Leitung von Prof. Altenmüller durchgeführt. Kooperationen bestanden mit der

Klinik für Neurologie und Humangenetik der Universität Lübeck (Frau Prof. Klein), der Klinik

für Neurologie der Universität Hamburg und dem Institut für Neuroinformatik der Universität

Bochum. Weitere Kooperationspartner waren das

Portland.

Medizinstudium

2001-2007 Medizinstudium an der Medizinischen Hochschule Hannover 2003 Physikum (Erstes Staatsexamen): Note -gut-

2007 Zweites Staatsexamen: Note -gut-

Famulaturen und Praktisches Jahr

2004 Innere Medizin Ev. Diakoniewerk Friederikenstift Hannover 2005 Neurologie Universitätsklinik Lübeck

Musikermedizin IMMM Hannover

2006 Neurologie Krankenhaus Henriettenstiftung Hannover 2006-2007 Praktisches Jahr in Hannover, Fächer: Neurologie, Innere Medizin und

Chirurgie

Dissertation

2004-2008 „Pathophysiologie der Musikerdystonie: Neuroplastizität und klinische Genetik“ am Institut für Musikphysiologie und Musikermedizin in Hannover

Doktorvater: Prof. Dr. med. E. Altenmüller

Ein Teilprojekt der Dissertation wurde durch den Dystonia Grant 2006 der Dystonia Medical Research Foundation und durch die Bachmann- Strauss Dystonia & Parkinson’s Foundation, Inc, unterstützt.

Beruflicher Werdegang

2006-2008 Anstellung als studentische Hilfskraft am Institut für Musikphysiologie und Musikermedizin in Hannover mit Aufgaben in Forschung und Lehre (Direktor: Prof. Dr. med. E. Altenmüller)

seit 2008 Arzt in der Klinik für Neurologie des Universitätsklinikums Lübeck (Direktor: Prof. Dr. med. D. Kömpf)

Auszeichnungen und Stipendien

2006-2008 als Studienkoordinator einer Studie der Dissertation durch den Dystonia Grant 2006 der Dystonia Medical Research Foundation und durch die Bachmann-Strauss Dystonia & Parkinson’s Foundation, Inc, finanziert 2007 Reisestipendium für die Teilnahme am Movement Disorder Society’s

(MDS) 11th International Congress of Parkinson's Disease and

Movement Disorders in Istanbul (Es wurden 35 Stipendien vergeben bei

ca. 1000 Posterpräsentationen.)

localized (involvement limited to one or two fingers) vs.

nonlocalized dystonia, type of dystonia (flexion, exten- sion, embouchure), task specificity at first visit, and duration of dystonia were no sufficient predictors.

BT injections were applied in 71 patients (49%), 3 of whom had embouchure dystonia. Eighteen patients had only one injection due to unsatisfying treatment results.

Five patients who reported an improvement were not satisfied enough to continue BT treatment. Fifty-three patients (37%) received more than one injection (aver- age, 5.7 injections per patients; range, 2–25) with an average treatment duration of 16 months (range, 1–58) and an average interval of 4.2 months (range, 1–22) between treatment sessions. The average dosage per treatment session was 128 units (range, 9 – 428). The most injected muscles were the flexor digitorum super- ficialis and the flexor digitorum profundus (each in 70%

of patients treated with BT), followed by the flexor carpi radialis (18%), the flexor pollicis longus, the extensor digitorum, and the extensor indicis (each 10%), and the interosseus palmaris (7%). The average dosage per mus- cle group was 112 units (range, 88 –150) in the upper arm and shoulder muscles, 38 units (range, 5– 85) in forearm extensors, 65 units (range, 10 –175) in forearm flexors, and 26 units (range, 5– 84) in hand muscles. After BT, an improvement was reported by 35 patients (49%) and by 30 patients who received more than one injection (57%

of these; average duration, 26 months). Of the latter group, 21 of 33 patients with injections given only in the forearm muscles reported an improvement (64%), and 7 of 13 patients with injections in the forearm muscles and hand muscles (54%) had an improvement: 2 out of 2 keyboard players, 2 of 4 woodwind players, and 3 of 4 guitarists with the right hand affected. No improvement was seen in the affected left hands of one guitarist and two string players after injections in the forearm muscles and hand muscles. None of two patients with injections in the upper arm/shoulder muscles experienced an im- provement and none of three patients with embouchure dystonia experienced an improvement. Multiple regres- sion analysis did not reveal any of the aforementioned variables as predictors of the outcome after BT. Positive rating of BT effects was correlated to the number of BT treatment sessions (Spearman r⫽ 0.37; P⬍ 0.01) and the duration of BT treatment (Spearman r⫽0.56; P⬍ 0.01).

Ergonomic changes were applied in 51 patients (35%

of all); 32 patients (63%) experienced improvement and used the ergonomic changes for an average of 35 months (range, 3–125). Two patients with embouchure dystonia used an ergonomic aid and reported no improvement.

Pedagogical retraining was applied in 24 patients (17%

of all); 12 patients (50%) experienced improvement and underwent this treatment for an average of 28 months (range, 3–72). Two patients with embouchure dystonia took part in pedagogical retraining and reported no im- provement. Seventy-eight patients (54% of all) were practicing nonspecific technical exercises; 44 patients (56% of these) experienced improvement. Six of 11 patients with embouchure dystonia reported an improve- ment after practicing such exercises.

DISCUSSION

Our results suggest that the situation in half of the patients with musician’s dystonia may be improved us- ing the currently available therapies. A treatment attempt with trihexyphenidyl appears to be an option for musi- cians with limb dystonia when no contraindications are present, although side effects are frequent and can lead to termination of treatment. BT injections in hand muscles appear to be recommendable only in instrumentalists with limited demand on lateral finger motion, such as in woodwind players and the right hand in guitarists. Key- board players may benefit from this option if they avoid repertoire requiring a wide hand span and extreme lateral finger motion. Ergonomic changes are used to prevent dystonic movements mechanically or to circumvent them by modification of key systems or by using support systems as described above. They were of benefit to 63%

of patients to which this option was applied and should be considered in all patients with limb dystonia.

The results underline the potential benefit of a behav- ioral approach either by pedagogical retraining or by self-guided exercises on the instrument. Only patients with limb dystonia improved with pedagogical retrain- ing. More than half of the patients who were practicing nonspecific exercises reported an improvement. This was the only beneficial treatment option for patients with embouchure dystonia, with 6 out of 11 patients reporting improvement. It is noteworthy that the results of these exercises were rated better than that of pharmacological therapies. These positive results may be biased by a particular attitude among musicians and the perceived self-control through exercises. On the other hand, results of retraining and exercises underlined the benefit of an active involvement of patients in the treatment process.

Therapy of patients with embouchure dystonia remains problematic. The available medical approaches are inef- fective, and other options have yet to be developed.

Beside the reported inclusion/exclusion criteria, the choice of treatment was strongly influenced by the pref- erences of patients. Time investment appeared to influ- ence the choice of treatment. Older patients who desired a quick improvement preferred BT injections. In con-

MUSICIAN’S DYSTONIA 1625

Movement Disorders, Vol. 20, No. 12, 2005

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