Sensory Trick in Musician`s Dystonia

Transcription

University of Veterinary Medicine Hannover
Institute of Music Physiology and Musicians' Medicine
Hannover University of Music, Drama and Media
Centre for Systems Neuroscience
Sensory Trick in Musician’s Dystonia:
the Role of Altered Sensory Feedback in Pianist’s Dystonia
THESIS
Submitted in partial fulfillment of the requirements for the degree
DOCTOR OF PHILOSOPHY (PhD)
awarded by the University of Veterinary Medicine Hannover
by
Felicia Pei-Hsin Cheng
Born in Taipei, Taiwan
Hannover, Germany [2014]
Supervisor: Prof. Dr. med. Eckart Altenmüller
1st Evaluation: Prof. Dr. med. Eckart Altenmüller
(Hannover University of Music, Drama and Media)
Prof. Dr. med. Karin Weißenborn
(Hannover Medical School)
Prof. Dr. rer. nat. Günter Reuter
(Hannover Medical School)
2nd Evaluation: Prof. Dr. rer. nat. Lutz Jäncke
(ETH and University of Zurich)
Part of the thesis has been published in:
Cheng, F. P. H., Großbach, M., & Altenmüller, E. O. (2013).
Altered sensory feedbacks in pianist's dystonia:
the altered auditory feedback paradigm and the glove effect. Frontiers in human
neuroscience, 7.
Date of final exam: 10 October 2014
Sponsorship:
Georg Christoph Lichtenberg Stipendium of Lower Saxony, Germany and
Studying Abroad Scholarship awarded by the Ministry of Education, Taiwan.
Contents
1
Summary
4
2
Introduction
9
3
Basic Concepts
13
4
Manuscript 1 (published content)
37
5
Manuscript 2
52
6
Conclusions and Outlook
70
7
References
73
Sensory Trick in Musician's Dystonia:
the Role of Altered Sensory Feedback in Pianist's Dystonia
1
Summary
Dystonia in pianists belongs to a group of dystonic movement disorders termed focal
dystonias. It is characterized by the degradation of voluntary control of highly skilled
movement patterns involved in piano playing. Previous studies have shown that apart from
being a movement disorder, many forms of focal dystonias involve several sensory
abnormalities, and cutaneous stimuli may temporarily reduce the severity of motor symptoms
in patients. The stimulus that may successfully reduce motor symptoms is termed sensory
trick. Studies on cutaneous sensory trick of focal neck dystonia suggested that sensory tricks
should be regarded as a complex dynamic mechanism that corrects the perceptual dysbalance
of the abnormal motor output.
The motivation for this dissertation came from anecdotal reports of organ players suffering
from musician’s dystonia who reported a signi ficant reduction of the motor symptoms when
playing on a pipe organ with delayed sound production after the key stroke due to mechanical
coupling of the keyboard and the organ pipes. The aim of the dissertation is to investigate the
possible underlying mechanism of these anecdotal reports by using altered sensory feedback
in both auditory and sensory modalities. The dissertation is divided into 2 parts:
The first part of the dissertation is based on behavioural studies of the effect of altered
auditory feedback in musician's dystonia (MD) and discusses whether altered auditory
feedback (AAF) can be considered as a sensory trick in MD. Furthermore, the effect of AAF
is compared with altered tactile feedback, which can serve as a sensory trick in several other
forms of focal dystonia. The results of the studies suggest that in the context of our
experimental designs, AAF and altered tactile feedback did not have a bene ficial role in
motor coordination in MD patients. We propose that altered auditory and tactile feedback do
not serve as effective sensory tricks and may not temporarily reduce the symptoms of patients
suffering from MD in this experimental context.
The second part of the dissertation continued with manipulating different sensory feedbacks
in the piano playing of healthy pianists and pianists suffering from MD. This study
investigated the impaired cortical functional network of pianists who suffer from MD by
employing altered auditory and altered tactile feedback during scale playing with
multichannel electroencephalography (EEG). By comparing the two groups under different
sensory feedback, the EEG data suggested a trend of higher degree of inter-regional phase
synchronisation between the frontal and parietal regions and between the temporal and
central regions in pianists suffering from MD in conditions that are relevant to the longtrained auditory-motor coupling (normal auditory feedback and complete deprivation of
auditory feedback), but such abnormalities are decreased in conditions with delayed auditory
feedback and altered tactile feedback. These findings support the hypothesis that the impaired
sensorimotor integration of MD patients is speci fic to the type of overtrained task that the
patients were trained for and can be modi fied with altered sensory feedback.
In conclusion, the results of the studies included in this dissertation showed that under our
experimental conditions, AAF cannot serve as a successful sensory trick in MD.
Nevertheless, both altered auditory and tactile feedback can induce different alternations to
the long-range inter-regional neural synchrony in MD patients and this may have an
implication for the task-specific deficit of inhibition in MD.
Der Sensorische Trick in der Musikerdystonie:
Die Rolle des veränderten sensorischen Feedbacks in der
Musikerdystonie
Zusammenfassung
Die Dystonie bei Pianisten gehört zu der Gruppe der fokalen aufgabenspezifischen
Dystonien, die durch den Verlust der feinmotorischen Kontrolle hochtrainierter
Bewegungsabläufe am Klavier gekennzeichnet ist. Frühere Studien haben gezeigt, dass die
Fokale Dystonie nicht nur durch eine Bewegungsstörung, sondern oft auch durch
verschiedene sensorische Abnormalitäten charakterisiert ist und dass die Ausprägung der
motorischen Symptome durch sensorische Stimulation bei Patienten manchmal
vorübergehend vermindert werden kann. Der Stimulus, der die motorischen Symptome
erfolgreich mindern kann, wird „Sensorischer Trick“ genannt. Studien über kutane
sensorische Tricks bei fokaler zervikaler Dystonie (Torticollis) haben ergeben, dass der
sensorische Trick als ein komplexer dynamischer Mechanismus gesehen werden kann, der
vorübergehend die Dysbalance abnormer motorischer Outputs korrigiert.
Die Motivation für diese Dissertation entstand durch einzelne Berichte von Orgelspielern, die
unter Musikerdystonie litten und von einer signifikanten Verbesserung der motorischen
Symptome durch verzögerte Tonproduktion nach dem Tastenanschlag beim Orgelspielen,
basierend auf der mechanischen Kopplung der Tastatur und der Orgelpfeifen, berichteten.
Das Ziel dieser Dissertation ist es, mögliche zugrunde liegende Mechanismen dieser
Einzelberichte mit Hilfe von verändertem sensorischen Feedback, insbesondere durch
Anwendung auditorischer und sensorischer Modalitäten, zu ermitteln. Die Dissertation ist in
zwei Teile gegliedert:
Der erste Teil der Dissertation beruht auf Verhaltensstudien, die den Einfluss des veränderten
auditorischen Feedback (VAF) auf die Musikerdystonie untersuchen und diskutiert, ob der
VAF als ein sensorischer Trick in der Musikerdystonie gesehen werden kann. Des Weiteren
wird die Auswirkung des VAF mit dem veränderten taktilen Feedback verglichen, der als
sensorischer Trick in einigen anderen Formen fokaler Dystonie dienen kann. Die Ergebnisse
der Studien weisen im Zusammenhang mit unserem Versuchsdesign darauf hin, dass sowohl
der VAF, als auch der veränderte taktile Feedback eine untergeordnete Rolle in der
motorischen Koordination der an Musikerdystonie erkrankten Pianisten spielen. Wir gehen
davon aus, dass weder der veränderter auditorische noch der veränderte taktile Feedback als
erfolgreicher sensorischer Trick dienen kann und dass diese, unserem Experiment zu Folge,
die Symptome der an Musikerdystonie leidenden Pianisten nicht mindern können.
Der zweite Teil der Dissertation setzt mit der Manipulation verschiedener sensorischer
Feedbacks während des Klavierspielens gesunder Pianisten und an Musikerdystonie
erkrankter Pianisten fort.
Dabei untersucht die Studie mithilfe der Multikanal-
Elektroenzephalografie (EEG) das abnorme kortikale funktionale Netzwerk der
Musikerdystonie- Pianisten durch Anwendung veränderter auditorischer und veränderter
taktiler Feedbacks während der Ausführung relevanter motorischer Aufgaben. Durch den
Vergleich der zwei Gruppen unter den verschiedenen sensorischen Feedbacks, zeigen die
EEG Daten bei Musikerdystonie- Pianisten eine tendenziell höhergradige inter-regionale
Phasensynchronisation zwischen den frontalen und parietalen Regionen, als auch zwischen
den temporalen und zentralen Regionen während Konditionen, die relevant für die lang
trainierte auditorisch- motorische Kopplung (normaler und tonloser auditorischer Feeback)
sind, jedoch sind solche Abnormalitäten vermindert bei Konditionen mit verspätetem
auditorischen und verändertem taktilen Feedback. Diese Ergebnisse unterstützen die
Hypothese, dass die beeinträchtigte sensomotorische Integration der MusikerdystoniePianisten spezifisch hinsichtlich der Art hochtrainierter Aufgaben ist und dass diese durch
veränderten sensorischen Feedback modifiziert werden kann.
Zusammenfassend zeigen die Ergebnisse der Studien in dieser Dissertation, dass unter den
experimentellen Bedingungen, VAF nicht als erfolgreicher sensorischer Trick in der
Musikerdystonie fungieren kann. Dennoch kann sowohl der veränderte auditorische als auch
der veränderte taktile Feedback zu verschiedenen Alternationen in der inter- regionalen
Synchronisation bei Musikerdystonie- Pianisten führen und dies kann eine Auswirkung auf
das aufgabenspezifische Defizit der Inhibition bei der Musikerdystonie haben.
2
Introduction
If, while at the piano, you attempt to form little melodies, that is very well;
but if they come to you of their own accord when not at the keyboard, you may be still more pleased;
for the music within has awakened .
The fingers must do what the head desires; not the contrary.1
Robert Schumann,
Advice to Young Musicians
The advice that Robert Schumann gave to young musicians remains invaluable to present-day
musicians, and is at the heart of many central research themes in the cognitive neuroscience
of music: musical memory, musical imagery, musical creativity, and the fine motor control
that defines expert music performance. Unfortunately, although Schumann displayed an
extraordinary piano technique early in his adolescence and attempted to become a concert
pianist, he developed a task-specific loss of voluntary control in the middle finger of his right
hand later in his life. Although it has long been shrouded in myth, Schumann’s motor control
problem has now been recognized as musician’s dystonia (MD) (Altenmüller 2006), which is
a form of focal dystonia that nowadays affects approximately 1% of all musicians.
1. Suchst du dir am Clavier kleine Melodien zusammen, so ist das wohl hübsch; kommen sie dir aber einmal
von selbst, nicht am Clavier, dann freue dich noch mehr, dann regt sich in dir der innere Tonsinn. – Die Finger
müssen machen, was der Kopf will, nicht umgekehrt. <<Musikalische Haus- und Lebens-Regeln>>, Robert
Schumann.
9
MD is a task-specific movement disorder which manifests itself as a painless muscular
incoordination or loss of voluntary control over extensively trained movements while playing
an instrument (Jankovic and Shale 1989; Lederman 1991; Brandfonbrener 1995; Frucht et al.
2001; Altenmüller 2003). Musicians suffering from MD show cramping or compensatory
movements that are highly disabling for their musical performance, and in many cases it is
necessary to terminate their musical careers, to which they have been devoted since
childhood.
Although dystonia clearly manifests itself as a movement disorder, it has been demonstrated
that several sensory dysfunctions are also involved in its pathophysiology. A very distinct
phenomenon related to sensory dysfunctions in dystonia is the sensory trick, which is also
one of the diagnostic criteria for dystonia. A sensory trick is a sensory input (cutaneous input
in previous studies) that can reduce the involuntary movements, abnormal postures or
associated feelings of pain in dystonic patients. It was first investigated in cervical dystonia
or spasmodic torticollis, a type of dystonia in which the muscles controlling the neck cause
sustained twisting or frequent jerking. Here, touching the face gently with the hand frequently
relieves symptoms remarkably. The physiological mechanisms behind this phenomenon are
still under discussion. In former times it was suggested that the sensory trick acts merely as a
static application of counterpressure or merely a change of the focus of attention, until
Naumann and his colleagues (2000) used PET as a method and proposed a model for the
mechanism of sensory trick, suggesting that patients suffering from cervical dystonia may use
their preferred sensory trick to restore spatial information and normalise their head position.
Similar to other forms of dystonia, MD also involves a wide range of sensory dysfunctions,
including altered temporal discrimination, altered feed-forward models for motor action, and
abnormalities in sensorimotor integration. However, the use of the sensory trick has never
been systematically investigated in MD. Jabusch et al. (2011) did mention the wearing of a
glove as a cutaneous sensory trick in musician’s dystonia, however the effect of wearing the
glove in MD was not the focus of the research in this study. What is even more important is
that, in previous studies, only cutaneous sensory tricks were investigated, and most studies
were carried out with patients suffering from focal dystonias that are not task-specific. In the
case of MD, it would be crucial to investigate the possibility of having an auditory sensory
trick, which can probe the over-trained yet abnormal auditory-motor integration. The
importance lies in the fact that this would be a new modality as opposed to the already welldocumented cutaneous sensory tricks, and explore the possible sensory trick repertoire within
MD.
10
The motivation for this project came from anecdotal reports from pianists, claiming that their
MD symptoms were reduced while playing on a pipe organ, which has a noticeable delayed
auditory feedback. However it was still not clear whether the improvement was brought about
by the different cognitive load resulting from an enhanced distal focus of attention, by the
delayed auditory feedback itself or by the altered tactile feedback of the different mechanism
of sound production. Another anecdotal report came from one of the musicians that brought
MD to public attention, the prominent pianist Leon Fleisher, who developed MD in the 60’s
(Fleisher and Midgette 2010). In Fleisher’s biography, he also mentioned a phenomenon that
is comparable to the tactile sensory trick (“… the idea of molding a foam pad around the ball
of my conductor’s baton: something that would reduce the tension of my death-grip on the
stick.”).
MD is a relatively under-studied form of focal dystonia, and I hope that this project can help
to shed light on the sensory dysfunction involved in MD and contribute to the research of
sensorimotor integration during expert music performance as well.
1.1. Thesis Outline
This thesis starts with a review of the basic concepts of motor systems, important aspects of
dystonia and a comprehensive overview of MD. Following the review, it is divided into two
main parts: The first part of the thesis is based on behavioural studies of the effect of altered
auditory feedback in musician's dystonia (MD) and discusses whether altered auditory
feedback (AAF) can be considered as a sensory trick in MD. Furthermore, the effect of AAF
is compared with altered tactile feedback, which can serve as a sensory trick in several other
forms of focal dystonia. The second part of the dissertation continued with manipulating
different sensory feedbacks in the piano playing of healthy pianists and pianists suffering
from MD. This study investigated the impaired cortical functional network of MD patients by
employing altered auditory and altered tactile feedback during scale playing with
multichannel electroencephalography (EEG) and the EEG analyses focused on the degree of
long-range phase synchronisation. The thesis concludes with a comprehensive discussion of
all the results.
11
1.2. Aims and Hypotheses
As a very first step in the investigation of the role of altered sensory feedback in MD, I hope
that this thesis might: (1) show the effect of altered sensory feedbacks in MD in a more
comprehensive way, and (2) help to elucidate the differences in long-range neural
orchestration between the healthy pianists and MD patients under different types of sensory
feedback during piano playing.
The following main hypotheses were to be tested:
1. Altered auditory feedback and altered somatosensory feedback may act as
successful sensory tricks in pianists suffering from MD (manuscript 1);
2. The degree of inter-regional phase synchronisation between the cortical regions
involved in the sensorimotor network is altered in MD patients (manuscript 2);
3. The patterns of such alteration are dependent on the sensory feedback
(manuscript 2).
12
3
Basic Concepts
3.1. Motor Systems:
Motor Cortex, Basal Ganglia, Cerebellum, and the Basal Ganglia –
Thalamocortical Circuitry
3.1.1. Basic Functional Principles of the Motor Systems
The motor systems consist of several neural structures, including the premotor and primary
motor cortices, the thalamus, the basal ganglia, the brain stem, the spinal cord, and the
cerebellum. They generate reflexive, rhythmic and voluntary movements. The generation and
control over voluntary movements are of particular interest in the present thesis, and therefore
will be emphasised in this chapter.
The main features of the motor systems that are involved in the generation of voluntary
movements (summarising and following Kandel et al. 1992) are as follows:
(1) The motor systems rely greatly on sensory information, and voluntary movements are
goal-directed and can be improved with practice as a result of feedback and feed-forward
mechanisms. In a feedback system, an incoming signal (sensory information) is compared
with a desired state, represented by a reference signal, and a comparator computes the
difference (error signal) for adjusting the motor output. In a feed-forward system, which is
13
widely used for controlling posture and rapid movements, the prior knowledge of the
movement generates anticipatory commands for the motor output before the feedback sensor
is activated. Feed-forward predictions of the action are thought to be generated by an internal
model (Wolpert et al. 1995) that receives an efference copy signal (prediction) of the motor
commands and integrates this with the current state of the system. The nervous system learns
to adjust for environmental perturbations by using both systems.
(2) The motor systems are organized hierarchically and have different control levels, with the
spinal cord at its lowest level, the brain stem at the next level, and the motor cortices at the
highest level. The motor cortex sends general motor commands to the lower levels, and the
commands are translated by the lower levels into the fine details (such as force and angle of
the joints) of the movement before being executed by the end effectors. In addition to the
three hierarchical levels, the cerebellum and basal ganglia also regulate the planning and
execution of movement, and they are both indispensable for the control of smooth movement
and posture. The basal ganglia - thalamocortical circuitry will be elaborated in the later part
of this chapter because of its importance in movement disorders.
(3) The motor systems function in a parallel way, which means that different descending
pathways (indirect and direct ones, and “descending” in a sense of hierarchical organization)
from the motor cortex to the spinal cord largely overlap in their final projection to the motor
neurons of the spinal cord. The indirect pathways travel from the motor cortex through the
brain stem to the spinal cord, while the direct ones travel via the corticospinal tract between
the pyramidal cells in the layer V of the pre- and postcentral gyrus in the cortex to the motor
neurons of the spinal cord.
3.1.2. Motor Cortex
The motor cortex participates directly in organizing and controlling the animal’s behavioural
repertoire (Graziano 2006). The large-scale organization of the motor cortex is somatotopic,
which means that it controls the movements of various body parts from somatotopically
organized cortical territories. This somatotopic organization is roughly maintained at
different hierarchical levels of the motor system. This concept of a simple map containing
representations of different body parts became the dominant view of the early twentieth
century (Penfield and Boldrey 1937; Fulton 1938). Throughout the decades, studies started to
provide evidence for a rough body map with some overlap between the representations of
different body parts, some disruptions in the representations and some multiple
14
representations (e.g., Donoghue et al. 1992). This evidence also suggests that the control of
voluntary movements emerges from the distributed networks of the primary motor cortex
(M1) rather than discrete representations, and in adult mammals these networks are
considerably plastic following pathological or traumatic changes and in relation to everyday
experience, including motor-skill learning and cognitive motor actions (Sanes and Donoghue
2000). The plasticity enables the motor cortex to operate at a much more complex level and
allows it to coordinate behaviourally useful actions. Embedded within this larger somatotopy,
more detailed representations can be found. For example, within the arm and hand
representation there lies a rough map of the hand location that can be obtained with electrical
stimulation (Graziano et al. 2002a,b). Overlap between these more detailed representations
has been shown as well (e.g. overlapping finger representations, Shieber and Hibbard 1993),
and the somatotopic representations in the motor systems would be better described
statistically due to the high variability of the maps across animal species and even across
individual animals within a species.
The simplistic “cortical view” states that there is also a hierarchy within the motor cortex.
According to this view, premotor areas are responsible for the motor planning at a higher
order, and the primary motor cortex (M1) breaks the motor plan down into elements that can
then be sent to the spinal cord for actual movement execution. It has been shown that the M1
(and the primary sensory cortex S1) is always activated by voluntary movement and therefore
it is suggested that M1 has a primary role in the execution of movements (Catalan 1998, both
simple and complex sequential finger movements), and it has been shown that M1 is
predominantly involved at the level of movement execution and plays a generally subservient
role in motor learning (Hardwick et al. 2013). In spite of this, Graziano (2006) has shown
that complex movements can also be generated by long impulse trains into M1 and the caudal
sector of the premotor cortex, and Kawashima et al. (1994) have shown that the M1 hand
area contains subregions that are related to preparatory activity and subregions that change
their activity with the learning new motor skills. Furthermore, it has also been argued that M1
is involved in the retention of learned movements via their repeated performance (e.g. de
Xivry et al. 2011). Since several models of motor learning consider muscle synergies to be
instrumental in reducing movement variability in later learning to allow improved levels of
skilled performance (e.g. Penhune and Steele 2012), it can thus be speculated that M1 may
play a role in motor learning through use-dependent mechanisms which are beyond the pure
executive function. All in all, although the precise mechanisms of M1 are still under debate,
its fundamental role in motor control is undebatable.
The premotor cortex (PMC) has various roles in sensory-motor processing: it is involved in
15
sensory-motor transformation due to its reciprocal connections to various posterior
association areas, with direct projections to the motor cortex that enable sensory-cued actions
to be realised; it contributes to sequencing behaviours by being involved in the generation of
sequences from memory (Halsband et al. 1993; Shibasaki et al. 1993; Sadato et al. 1996),
motor learning (Jenkins et al. 1994; Janata and Grafton 2003) and action selection (Deiber et
al. 1991; Koechlin and Jubault 2006). There is functional lateralization of PMC in the context
of different aspects of motor learning, and PMC can be divided into dorsal (dPMC) and
ventral (vPMC) sectors. Regarding its functional lateralization, it has been suggested that the
left PMC is activated during sequence acquisition, while the right PMC is involved during
more advanced stages of learning and in storage of sequences (Schubotz and von Cramon
2003). Furthermore, the right PMC has been found to be active when participants learn purely
perceptual components of the serial response time task (Schubotz and von Cramon, 2002 a,b).
Regarding the division between dPMC and vPMC, generally speaking, it has been proposed
that they are involved in direct and indirect visuomotor transformations respectively (Hoshi
and Tanji 2006, Hoshi and Tanji 2007). In auditory-motor interactions in music perception
and production, it has been proposed that vPMC is likely to activate motor programs during
music listening. This is based on the studies showing that some mirror/echo neurons in
vPMC can be activated by the associated sound produced during the action, similar to how
they respond to action - visual representations/observations of actions (Rizzolatti et al. 2001;
Kohler et al. 2002). In contrast to vPMC, dPMC may be a crucial node for extracting higherorder metrical information which allows temporal expectancies to be formed (Zatorre et al.
2007) – a key to musical understanding and appreciation (Huron 2006).
Similar to M1, the supplementary motor area (SMA) is also frequently activated during the
execution of movements, but it has a more specific role in the self-initiation of voluntary
movement (Deecke and Kornhuber 1978; Deiber 1996). SMA might also take part in the
preparation of internally referenced or memorized motor acts through selective activity for
specific sequences of actions and code for the intervals between actions in a sequence (Mita
et al. 2009), whereas pre-SMA code for their rank-order and is primarily involved in
sequence initiation and sequence chunking (Kennerley et al. 2004) and can also be activated
during non-motor cognitive tasks such as conflict-monitoring (Nachev et al. 2008).
Furthermore, SMA has a crucial role in motor imagery since previous studies have shown
that when both expert musicians were asked to imagine performing and non-musicians were
asked to listen to a newly acquired piece, the SMA and premotor areas are recruited
(Langheim et al. 2002; Lahav 2007).
Briefly summarising, both the PMC and SMA have been reported to engage in the generation
16
of memorised, temporally planned complex motor sequences, which is one of the
prerequisites of music production.
3.1.3. Basal Ganglia
The basal ganglia (BG) consist of four nuclei, playing a major role in the regulation of
normal voluntary movement. Unlike most other components of the motor system, the BG do
not have direct input or output connections with the spinal cord. These nuclei receive their
primary input from the cortex and output to the brain stem, and via the thalamus, back to the
prefromtal, premotor, and motor cortices. (see section 2.1.5. for BG-thalamocortical circuits).
The four principal nuclei of BG are: (1) the striatum (consisting of the caudate nucleus, the
putamen, and the ventral striatum) (2) the globus pallidus (or pallidum, which can be divided
into external and internal segments) (3) the substantia nigra (consisting of the pars reticulata
and pars compacta) (4) the subthalamic nucleus.
The clear importance of the BG in motor control was first stressed in clinical observation.
Postmortem examination of patients with Parkinson’s disease, Huntington’s disease, and
hemiballism revealed pathological changes in these subcortical nuclei, with characteristic
motor disturbances such as tremor, involuntary movements, changes in posture and muscle
tone, and slowness of movements (without paralysis), or a combination of these disturbances.
Concerning the significant role of BG within the context of motor control, one wellestablished hypothesis states that there are competing motor programs, and the role of the BG
is to facilitate desired, adaptive motor commands and inhibit the other ones that would
interfere with the desired movement. Simultaneously, inhibition is removed focally from the
desired motor commands. Inability to inhibit competing motor programs results in slow
movements, abnormal postures and involuntary muscle activity and this well explains the
characteristics of various movement disorders. BG themselves do not generate movements,
voluntary movement is generated by cerebral cortical and cerebellar mechanisms (Mink
1996; Mink 2003).
Another well-established hypothesis within the context of motor control states that BG plays
a significant role in habit and stimulus-response learning. The modular corticostriatal
projection patterns are viewed as producing templates suitable for the gradual selection of
new input-output relations in cortico-BG loops, and within BG (striatum) representations of
habit and cognitive action sequences can be chunked and implemented as performance units
17
(Graybiel 1998). This hypothesis elaborates Miller’s notion (Miller 1956) of sensorimotor
chunking.
In addition to motor disturbances, cognitive and behavioural disturbances may also occur as a
result of damage to the BG, reflecting the association of BG to the frontal lobes (Graybiel
1997). The role of BG in decision making (action and conflict monitoring) has also been
shown (Basso and Wurtz 2002; Frank 2006).
3.1.4. Cerebellum
The extremely ordered cytoarchitecture and the simplicity of cell types (only five types of
neurons) of the cerebellum have long been a major attraction for the theorists and the
modellers, but until today our understanding of its anatomical structures far exceeds that of
its functional roles. Traditionally, the cerebellum has been considered as an essential structure
receiving information from the periphery, acting on the motor cortex and the brain stem in
order to monitor movement. However, in recent decades evidence has emerged showing that
the cerebellum also participates in high level cognitive processes (Schmahmann and Sherman
1998). Cerebellar cognitive affective syndrome (CCAS) includes impairments in executive,
visual-spatial, and linguistic abilities, with disturbance ranging from emotional blunting and
depression, to disinhibition and psychotic features (Schmahmann 2004).
In the context of motor learning and motor control, one of the most well-established
hypotheses states that t h e cerebellum acts as the hub for internal models of t h e motor
apparatus (Wolpert et al. 1998). It is proposed that the cerebellum contains multiple pairs of
corresponding forward and inverse models, each instantiated within a microzone of the
cerebellar cortex consisting of an inverse model of a specific controlled object such as the eye
or arm. The modular and repetitive cytoarchitecture would include the forward and inverse
models of the previous sections. The major advantage of this hypothesis is that internal
models provide a firm computational foundation from which theories about the roles of the
cerebellum in motor learning and motor control can be considered (see MOSAIC models,
Haruno et al. 2001 and Wolpert et al. 2003).
3.1.5. The Basal Ganglia - Thalamocortical and Cerebello-Thalamocortical Circuits
Following sections 3.1.2. to 3.1.4, this section aims to provide a more integrated view of the
18
BG-thalamocortical and cerebello-thalamocortical circuits because of their importance in the
pathogenesis of hypokinetic movement disorders such as Parkinson’s disease and
hyperkinetic movement disorders such as dystonia, hemiballismus, and Huntington’s chorea.
The circuits are also involved in non-motor functions.
The nuclei of the BG function as components of several segregated parallel circuits (for a
classic review see Alexander et al. 1986), and models have been proposed for the
corticostriatal connectivity and can be characterized by parallel circuits from the cortex to
three functional subdivisions of the striatum into associative, motor (skeletomotor and
oculomotor) and limbic circuits (Postuma and Dagher, 2006).
Figure 3.1 schematically summarises the BG – thalamocortical circuits (reproduced from
Walter and Vitek 2012). The BG receive inputs from motor and non-motor areas of the entire
cortex to the striatum and outputs to more than a single cortical area via the thalamus (Akkal
et al. 2007). In the case of motor circuit, cortical inputs from precentral motor and postcentral
somatosensory cortices project onto the posterior putamen. Subnuclei of the thalamus also
project onto the striatum, with cerebellar information integrated into the BG circuit. The
internal segment of the globus pallidus (GPi) and substantia nigra pars reticulate (SNr) serve
as the predominant output nuclei of the BG.
Considering the input and output areas of BG anatomically, there are two parallel pathways:
(1) the direct pathway that originates in the striatum projects directly to the output nuclei GPi
and SNr and (2) the indirect pathway that originates from striatum as well, but projects to the
external segment of the globus pallidus (GPe) then projects to the subthalamic nucleus (STN)
and finally in turn projects to the GPi and SNr. There is also a “hyperdirect” pathway which
consists of somatotopically organised projections onto the STN from the cortical
sensorimotor areas that project to the putamen. All the 3 pathways have a final common
output through GPi and SNr which projects to the thalamus and brainstem.
Functionally, it has been proposed that the BG-thalamocortical motor circuit may function to
scale and focus motor activities. Scaling of movement is implemented through balancing the
excitatory and inhibitory mechanisms of the direct and indirect pathways. Increased direct
pathway activity would lead to increased inhibition of GPi neurons and promote movement
through disinhibition of movement-related neurons, while increased indirect pathway activity
would suppress movement by increasing excitatory activity from the STN to the GPi and
increasing inhibition of movement-related thalamocortical neurons. Focusing of movement is
implemented through different pathway projections onto different neurons. The
19
aforementioned hypothesis (in section 2.1.3.) of “the competing motor program” proposed by
Mink is consistent with the abovementioned BG-thalamocortical function. Based on this
hypothesis, the desired voluntary movement is selected by the cortical area, and it activates
the direct pathway while competing programmes are inhibited by the cortical projections
through the indirect and hyperdirect pathways.
Figure 3.1
Basal Ganglia – Thalamocortical circuitry
(reproduced from Walter and Vitek 2012)
Excitatory projections are represented with gray arrows and inhibitory projections are represented with black
arrows. GPE globus pallidus par externa, GPI globus pallidus interna, STN subthalamic nucleus, SNR
substantia nigra pars reticulate, PPN pedunculopontine tegmental nucleus, MEA mesencephalic extrapyramidal
area. Thalamic subnuclei: VA ventralis anterior, VLo ventralis lateralis pars oralis, VPLo ventralis posterior
lateralis pars oralis, CL central lateral, CM centromedian, Pf parafascicular.
20
3.2 Expert Piano Performance :
A Distributed Network and Auditory-Motor Integration
I n t he research field of neural network and t he auditory-motor integration of music, the
piano/keyboard is widely used because it is methodologically convenient. Amongst others,
due to MIDI-technology, it is more feasible to employ the piano for combining parametercontrolled laboratory set-ups than other musical instruments (Bangert 2006).
One of the earliest functional neuroimaging studies on piano performance (PET study,
Sergent et al. 1992) showed that the cortical areas involved in the performance of sightreading sheet music are distinct from, but adjacent to those underlying similar verbal
operations. Since then, various paradigms and neuroimaging techniques were used for the
investigation of cortical areas involved in piano playing. Over the years, cortical areas
including pre-motor areas, SMA, M1, the dorsolateral pre-fontal cortex (including Broca’s
area in both hemispheres), and the posterior parietal cortex have been confirmed to be
involved in the neural network of piano playing (ex. Jäncke et al. 2000; Krings et al. 2000;
Itoh et al. 2001 , Baumann et al 2005; Baumann et al 2007; for a review, see Jäncke 2006).
But how these cortical areas are dynamically orchestrated was still the subject of speculation,
therefore more investigation into auditory-motor integration was, and still is needed.
Auditory-motor integration is a form of sensorimotor integration, which is a dynamic process
that combines different sources and modalities o f sensory information and transforms such
information into motor actions. The well-established auditory-motor integration is
undoubtedly one of the crucial neural mechanisms that support expert music performance. It
is only when the fundamental auditory-motor integration is established that the expert
musician can perform at an automated level and focus on the interpretation, expressivity or
other higher musical aspects and convey their musical ideas to the listeners
Similar to the classical reach-and-grasp examples, studies of auditory-motor integration are
also largely built upon the concept of feed-forward and feedback interactions. The feedforward mechanism is particularly important for pitch accuracy and temporal precision for
the rapid, complex musical sequence production. In feed-forward control of movement, the
anticipatory auditory imagery modulates the motor output in a predictive manner. It has been
shown that musicians have a better developed anticipatory auditory imagery than nonmusicians, suggesting that musical training plays a major role in the formation of auditory
imagery (for pianist-related studies, see Bangert et al. 2006; D’Ausilio et al. 2006; Baumann
21
et al. 2007; and for the acquisition by non- musicians of similar neural mechanisms for
keyboard playing, see Lahav et al. 2007). Moreover, internal feed-forward models can predict
the next state of a system from its current state and motor command, and are thus crucial for
continuous error-monitoring (Ruiz et al. 2009). Feedback interactions are more important for
musical tasks in which pitch is variable, such as playing a string instrument or singing. In the
context of piano studies, most studies on altered auditory feedback were done via distorting
the temporal or/and pitch association with the keyboard/events created by finger action
(Pfordresher 2006). It has been shown that motor planning can be seriously disrupted by
altering the auditory feedback: asynchronous feedback can disrupt the timing of action, and
mismatched pitches can disrupt the selection of appropriate action. As for the complete
deprivation of auditory feedback, it does not affect the execution of well-rehearsed motor
sequences, which again shows the importance of feed-forward mechanism. It has been
suggested that the fine-tuning (expressivity) and control of pedalling rely more on the
auditory feedback (Repp 1999).
There are several models of auditory-motor interactions, yet most of them were proposed for
avian “song system” sensorimotor learning (ex. Brainard and Doupe 2000; Bolhuis and Gahr
2006) or human speech processing (ex. Hickok and Pöppel, 2004; Guenther 2006). A general
model for auditory-motor transformations (vocal sound) was proposed by Warren and her
colleagues (2005), describing an auditory “do-pathway” in which the posteromedial superior
temporal plane generates sequenced auditory representations by matching incoming auditory
information with stored templates, and subsequently used to constrain motor responses.
Following this study, a recent fMRI study using an fMRI-compatible keyboard was carried
out by Chen and her colleagues (2012), and they proposed that this auditory-motor
association is related to the reduction of activity in the dorsal action stream of auditory
processing, which maps auditory feedback onto motor-based representations. Brain areas
such as the premotor cortex and the posterior superior temporal gyrus (pSTG) are included in
this dorsal action stream, and it is suggested that the reduction of activity reflects increased
efficiency in the neural network for the learned stimulus. This in a way confirms the previous
finding of Warren et al. (2005) and the findings which indicated a decrease in cerebral
activation in pre-motor and motor areas when professional pianists are compared with nonmusicians performing the same movement (Jäncke et al. 2000; Krings et al. 2000).
22
3.3 Dystonia
3.3.1. History and Definition
Dystonia is a rare, fascinating disorder not only because it manifests itself with impressively
unusual involuntary movements and postures, but also because of its relevance to the
mechanism of (deficient) movement preparation and execution. The first description of
dystonia has been credited to Destarac, who, in 1901, reported a woman who developed
torticollis, tortipelvis, writer’s cramp and spasmodic talipes equinovarus (Zeman and Dyken
1968). It has been just 100 years since Oppenheim coined the term “dystonia” in 1911 (Klein
and Fahn 2013). Nevertheless, for much of the 20th century, dystonia was assumed to have a
psychiatric or functional origin (Lanska 2010). Only after Marsden’s seminal observation in
the 1970s did it become clear that blepharospasm, oromandibular dystonia, dystonic writer's
cramp, torticollis, axial dystonia and several adult-onset dystonias share a common
underlying substrate (Marsden 1976). The research of dystonia has been rather challenging
due to its heterogeneous symptoms and richer phenomenology compared to other forms of
movement disorders.
The general definition of dystonia has gone through several modifications with over a
century’s clinical and scientific progress. Presently it is defined as “a movement disorder
characterized by sustained or intermittent muscle contractions causing abnormal, often
repetitive, movements, postures, or both.“ (from Albanese et al. 2013, which is a
modification of the most widely used classic definition proposed by Fahn 1988). The need for
a revised definition for dystonia and an algorithm for diagnosing/evaluating patients has also
been proposed (Frucht 2013).
Dystonic movements are typically patterned and twisting, and may be tremulous. There are
several features that distinguish dystonia from other hyperkinesias, the most important one
being its characteristic directionality, often involving the simultaneous activation of agonist
and antagonist muscles, producing a recognisable, predictable posturing or twisting
movement (referred to as patterning) (Svetel et al. 2004). In many dystonic patients, the
“involuntary” movements are brought about by attempted voluntary movements (Hallett,
2000) and may only be triggered by very specific tasks. The repertoire of movement that
induces dystonia in the affected area may extend to activity in remote body parts, and in
severe cases, dystonia may progress and even occur at rest. (Shankar and Bressman 2012).
23
3.3.2. Classification
According to the most up-to-date report based on the consensus of a group of investigators
with extensive experience in this field, dystonia is “classified along 2 axes: clinical
characteristics, including age at onset, body distribution, temporal pattern and associated
features (additional movement disorders or neurological features); and etiology, which
includes nervous system pathology and inheritance.” (Albanese et al. 2013).
Dystonia can have any age onset. Primary dystonia has a bimodal distribution, with modes at
9 (early-onset) and 45 years old (late-onset) (Bressman et al. 1989). Age of onset (and first
affected site) is also associated with disease progressions or spread. Dystonia is more likely
to progress to many body parts with an early-onset. For example, children having onset in a
leg or arm often have the disease progress within 5-10 years to generalised dystonia involving
multiple limbs. Marsden and Harrison (1974) stressed age at onset as the single most
important feature in determining outcome. The earlier the age at onset, the more likely
symptoms will be severe, with dystonia spreading to involve multiple regions. Unlike the
early-onset, the late-onset dystonias are more likely to be focal and localised. Therefore, the
classification of age onset can be used as a guideline to predict the possible disease progress
(Greene et al. 1995).
There are five subclasses of body distribution, based on a hierarchical scheme describing the
extent of body region(s) affected: focal, segmental, hemidystonia, multifocal, and generalised
(Bressman 2004), and focal dystonia (FD) is the most common form among all five. FD
manifests in muscle contractions in a single body region, examples of FD include
blepharospasm, oromandibular dystonia, laryngeal dystonia (spasmodic dysphonia), focal
hand dystonia (FHD, for example, writer’s cramp and musician’s dystonia, which is at the
heart of this thesis), cervical dystonia (torticollis). FD may also spread, and it usually
involves one or more contiguous body regions, termed segmental dystonia, as opposed to
multifocal dystonia, which has a non-contiguous distribution of affected regions.
Hemidystonia is a type of multifocal dystonia that involves the ipsilateral arm and leg and is
almost always a secondary dystonia (see the paragraphs for etiology). Generalised dystonia
involves both legs or one leg and the trunk plus at least one other body region, which is
usually the arm(s) (Shankar and Bressman 2012).
Etiologically, dystonia can be categorised into two groups: primary (idiopathic) and
secondary (symptomatic), and treatment can best be guided by its etiology. Primary dystonia
comprises a group of clinical syndromes that are known or likely to have a genetic basis. It
24
develops spontaneously in the absence of any apparent cause or associated disease and shows
no other neurological symptoms, except tremor and myoclonus (Breakefield et al. 2008).
Several forms of primary dystonia are paroxysmal (with sudden onsets) with dyskinesia
(which may be dystonic, repetitive or choreiform) and can be triggered by the intake of
specific substances, stress or repetitive movements; they might also have epileptic features.
Secondary dystonia comprises syndromes in which dystonic symptoms result from other
disease states or brain injury. The manifestations and causes of secondary dystonias vary
widely, ranging from monogenic (if being a result of another neurodegenerative hereditary
disorder), environmental and complex causes.
3.3.3. Pathophysiology
There are three general abnormalities that appear to underlie the pathophysiological substrate
of dystonia: (1) loss of inhibition (2) sensory dysfunction (3) derangement of plasticity
(Quartarone and Hallett 2013).
(1) loss of inhibition
The loss of inhibition might have contributed to the loss of selectivity of movement and
overflow characterised in dystonia, and it may have also contributed to loss of ability in
movement imagination (Quartarone et al. 2005) and in inhibition of a pre-planned response
(Stinear and Byblow 2004b). Alterations of inhibitory circuits were found at several levels of
the motor systems, including the spinal cord, brainstem, and cortex (Berardelli et al. 1998;
Hallett 2011). In patients with FHD, the reciprocal inhibition between agonist and antagonist
muscles is reduced (Nakashima et al. 1989; Panizza et al. 1990). This abnormality may in
turn lead to the altered processing of afferent input to the spinal cord or abnormal supraspinal
control of the spinal interneurons mediating presynaptic inhibition in the spinal cord (Defazio
et al. 2007). Surround inhibition has also been reported to be abnormal in patients with FHD
(Sohn and Hallett 2004) and might have contributed to the overflow to inappropriate muscle
groups. The abnormal surround inhibition might be a consequence of the lack of intracortical
inhibition, as demonstrated in several TMS studies (see Hallett 2011 for a review). It is worth
noting that although the symptoms usually appear to be unilateral, the abnormal intracortical
inhibition may be found in both hemispheres.
Anatomically, the loss of inhibition has been interpreted as basal ganglia dysfunction. One of
25
the hypothesis, supported by emerging evidence, suggests that there are physiological
changes in the pallidum and thalamus (see Figure 3.2, which can be compared to part of the
healthy BG-thalamocortical circuitry in Figure 3.1). In generalised dystonia, there is a
decrease in the mean discharge rate of GPi neurons and enhanced synchrony at low
frequencies (Vitek et al. 1999). The imbalance in the direct and indirect pathways may have
lead to the abnormal surround inhibition.
Figure 3.2
A model proposed for dystonia (reproduced from Walter and Vitek 2012).
Increased mean firing rates of neurons are represented with wider arrows, while decreased rates are represented
with thin arrows. Increased neural synchronicity is represented in disrupted lines.
While a number of investigators are in favour of the abnormal BG-thalamocortical circuitry
hypothesis, some have pointed out that the cerebellum may play a role by influencing the
cortical excitability (ex. Brighina et al. 2009). The mechanisms explaining the loss of
inhibition remain debatable.
(2) sensory dysfunction
Besides the apparent movement dysfunctions, sensory dysfunction is also a main feature of
dystonia and often precedes the obvious motor symptoms (ex. Suttrup et al. 2011). Studies
have shown that the following sensory functions are compromised in patients with primary
dystonias: (1) temporal discrimination and integration of sensory stimuli (Tinazzi et al. 1999;
Bara-Jimenez et al. 2000; Sanger et al. 2001; Tinazzi et al. 2004; Fiorio et al. 2007; Fiorio et
al. 2008); (2) spatial discrimination of tactile stimuli (Sanger et al. 2001; Bara-Jimenez et al.
2001; Molloy et al. 2003; Peller et al. 2006); (3) vibration-induced illusion of movements
(Grünewald et al. 1997; Rome and Grünewald 1999; Yoneda et al. 2000; Frima et al. 2003);
and (4) movement representation and learning (Ghilardi et al. 2003; Fiorio et al. 2006; Fiorio
et al. 2007; Fiorio et al. 2008).
26
The deficits in the BG, the cerebellum and the sensory cortex may all play a role in the
sensory abnormalities in dystonia. Considering BG-thalamocortical circuits, the striatum has
an influence on the BG output to the thalamus and back to motor cortical areas, therefore
abnormalities in the BG may cause improper sensory gating, resulting in altered filtering of
the sensory information provided to the motor system (Murase et al. 2000; Kaji 2001). The
cerebellum may affect the somatosensory threshold in the cortex as the result of receiving
direct input from the spinal cord and can influence the cortical excitability (Daskalakis et al.
2004; Ben Taib et al. 2005). Moreover, some studies have shown that abnormalities may be
directly located in the sensory cortex. A lack of short-latency intracortical inhibitory
mechanisms has been shown with an abnormal somatosensory-evoked potential recovery
curve (Tamura et al. 2008), and disorganisation of the normal homuncular finger
representations in the primary sensory cortex has also been shown in patients with taskspecific dystonias (Bara-Jimenez et al. 1998; Elbert et al. 1998; Meunier et al. 2001), which
might be a result of reduced surround inhibition.
(3) derangement of plasticity
Maladaptive plasticity is one of the features for the pathogenesis of dystonia (Quartarone et
al. 2006; Quartarone and Pisani, 2011), and it plays a particularly important role in FHD. It
has been shown in a primate model that overtraining of a specific hand movement can induce
dystonia-like motor impairment (Byl et al. 1996), and in humans FHD is typically triggered
by period of intensive training of a particular movement (Roze et al. 2009; or see the next
section on musician’s dystonia). However, overtraining in specific hand movements only
induces FHD in some subjects, while most subjects are completely healthy. This leads to the
hypothesis that subtle abnormalities of plasticity may render certain individuals more
susceptible to dystonia, and the repetitive overtraining is a detrimental influence that helps to
push this maladaptive plasticity to the extreme. Therefore, it has been proposed that both the
use-dependent environmental factors and abnormal mechanisms of plasticity within the
sensorimotor circuits be taken into consideration with regard to the pathogenesis of FHD
(Quartarone et al. 2003; Altenmüller and Jabusch 2010).
A number of transcranial magnetic stimulation (TMS) studies have shown an abnormal
responsiveness in both the motor and sensory cortices in various primary dystonias (Edwards
et al. 2006; Weise et al. 2006; Quartarone et al. 2008; Tamura et al. 2009). To show that
plasticity is impaired in dystonia, paired associative stimulation (PAS) has been used to
demonstrate that both long-term potentiation-like and long-term depression-like facilitatory
and inhibitory effects on the TMS-evoked motor evoked potentials (MEPs) recorded from the
27
target muscles are enhanced in patients with FHD (Quartarone et al. 2003; Weise et al. 2006).
Since it has been proposed that homeostatic plasticity is an essential requirement to maintain
overall synaptic weight in neuronal networks within a useful dynamic range (Turrigiano et al.
1998), it has also been proposed that the abnormally enhanced plasticity in dystonia might be
the result of a disruption of homeostatic plasticity within the sensorimotor circuits
(Quartarone et al. 2005; Jung and Ziemann 2009).
3.3.4. Sensory Trick
Following the aforementioned paragraphs on sensory dysfunctions in dystonia, I would like
to continue with a very distinct phenomenon, which is also a diagnostic criterion for dystonia
– the sensory trick. Sensory manipulation is known to modify (induce or attenuate) dystonic
symptoms. The most distinctive sensory phenomenon of focal dystonia is that in some
patients the involuntary movements, abnormal postures or associated feelings of pain can be
reduced or eliminated by the application of cutaneous stimulation, such as touching the
involved or adjacent body part. This puzzling phenomenon is also commonly termed “geste
antagoniste”. Early in the 1890s, Brissaud already documented several observations of
sensory tricks in patients with cervical dystonia (Brissaud 1895). In Oppenheim’s 1911 paper
it was also well documented that a young 16-year-old patient was able to walk less
unnaturally when he rested with his hands on the knee area, which is also suggested as one of
the first descriptions of geste antagoniste (Klein and Fahn 2013).
To date, most studies on the sensory trick phenomenon focus on the characteristics and
systematic assessment of the cutaneous trick effect, particularly for cervical dystonia (Leis et
al. 1992; Wissel et al. 1999; Naumann et al. 2000; Müller et al. 2001), blepharospasm
(Gómez-Wong et al., 1998), and jaw-opening dystonia (Schramm et al. 2007). A study by
Filipović et al. (2004) devised a questionnaire that evaluated the self-reported data provided
by the patients, further investigated the global features of the clinical effect and detailed the
phenomenology of the sensory tricks.
Although the clinical features of the sensory tricks have been well-documented, the
physiological mechanisms behind this phenomenon are still under discussion. In former times
it was incorrectly suggested that the sensory trick acts merely as a static application of
counterpressure or merely a change of the focus of attention. Recent studies have shown that
the sensory tricks play an important role in the sensorimotor integration of the modulation of
the abnormal motor programme. An elegant PET study on cervical dystonia (Naumann et al.
28
2000, to my knowledge the only neuroimaging study explicitly to put an emphasis on the
sensory trick) reported the effect of the sensory trick on the cortical activation pattern,
showing that the trick manoeuvres lead to an increased activation mainly in the superior and
inferior parietal cortex, and also lead to decreased activation of the supplementary motor area
and the primary sensorimotor cortex. The authors suggested a model in which the sensory
tricks act as a way to restore spatial information, and with this restoration the dystonic head
position is corrected to the normal position. In other words, this model describes the
successful sensory tricks as perceptual dysbalance to the abnormally defined head posture
caused by long-term dystonic head deviation, mediate distinct sensorimotor transformations
and result in the correction of head position.
Another study by Schramm and colleagues (2004) used different locations for cutaneous
stimuli, different materials and even different types (cutaneous input, imagination and raise
arm) of sensory tricks to further investigate the mechanism of sensory tricks. A similar twophase model for sensory tricks in cervical dystonia was proposed: in the first phase of trick
manoeuvre, normalization of head posture is obtained by counterpressure or volitional
antagonistic muscle activity, and in the second phase, this position can be further stabilized
using sensory tricks challenging the central adaption of the distorted sensorimotor integration.
This again showed that sensory tricks should be regarded as a complex dynamic mechanism
that is executed at higher levels of sensorimotor integration since the trigger mechanisms of
sensory tricks are rather unspecific (e.g. the effect of the side and location of the trick
application play a minor role) and even imagination could help to normalize the head posture.
The authors also suggested that based on this model, adaptive motor learning strategies can
be considered as a part of the treatment.
3.3.5. Treatment
The assessment of therapeutic intervention in dystonia is often challenging for several
reasons: (1) it is difficult to quantify the dystonic effect on the functions; (2) the etiologies
and anatomic distributions are complex, and clinical manifestations are heterogeneous; (3)
some patients show spontaneous, transient remissions; (4) dosages of pharmacological
treatment may have been insufficient or the follow-up was too short to assess the benefit; (5)
most studies of therapeutic trials are not double-blinded and placebo-controlled and; (6) in
most studies, patient sample sizes for assessment are usually inadequate (Jankovic 2013).
Therefore, the selection of choice of therapy is largely based on personal experience and by
empirical trials.
29
The commonly adopted treatments for dystonia can be categorised into: (1) physical,
supportive, and ancillary therapy; (2) pharmacological treatment; (3) chemodenervation with
botulinum toxin; and (4) peripheral and central surgery (Jankovic 2013; Moro et al. 2013).
(1) physical and supportive therapy
There are several paramedical interventions reported to be useful for primary dystonia
(Delnooz et al. 2009), including: custom-designed devices that can act as a successful
sensory trick (Abbruzzese and Berardelli 2003), immobilising apparatus (which may however
also increase the risk of peripherally-induced dystonia, see Jankovic 2009) or constraintmovement therapy (ex. Candia et al. 2002), sensory (re-)training (Zeuner and Hallett 2003;
Zeuner et al. 2008), repetitive transcranial magnetic stimulation (rTMS) and transcranial
direct current stimulation (Wu et al. 2008; Benninger et al. 2011). Interestingly, it has been
reported that sensory cortical representation of the hand may be restored after participating in
a wellness programme that offered aerobics, postural exercises, and carried out supervised,
attended, individualized, repetitive sensorimotor training activities for at least once per week
for 12 weeks (Byl et al. 2003). Combinations of physical and supportive therapy with
pharmacological treatment are commonly used as well (Delnooz et al. 2009).
(2) Pharmacological treatment
Pharmacological treatment of dystonia is based largely on an empirical rather than scientific
rationale, except for the treatment of dopa-responsive dystonia, in which the underlying
mechanisms have been well-elucidated. Pharmacological options include: dopaminergic
therapy, antidopaminergic therapy, anticholinergic therapy, and baclofen (Jankovic 2013). A
combination of several medications is required for most of patients (Jankovic 2009).
(3) Botulinum Toxin
Since it’s revolutionary introduction in the late 1980s, botulinum toxin (BoNT) remains the
most powerful treatment of dystonia until now. It is the most commonly adopted therapeutic
tool in treating various disorders involving abnormal, excessive, inappropriate muscle
contractions or increased secretions (Jankovic et al. 2009; Thenganatt and Fahn 2012). The
mechanism of action of BoNT is due to its ability to cause chemodenervation (blocking the
transmission of nerve impulses to the muscle) and to produce local paralysis when injected
into a muscle. It has also been hypothesised that via altering the peripheral sensory feedback,
30
BoNT may potentially produce reorganisation of the intracortical circuits, which may in turn
lead to altered excitability of the motor cortex (Gilio 2000).
(4) surgical treatment
Deep brain stimulation (DBS) is an invasive method for treating generalised and segmental
dystonias. It mimics the effect of thalamotomy and pallidotomy by implanting electrodes that
mainly target GPi and STN (Yianni et al. 2011). The benefit of DBS in focal and secondary
dystonias is still under research, yet its effectiveness in Parkinson’s disease (PD) and
generalised/segmental and cervical dystonia is striking (for PD, see Ghika et al. 1998; Krauss
et al. 1999; Coubes et al. 2000; Eltahawy et al. 2004; ). A randomised, sham-controlled study
showed that DBS that targeted at bilateral GPi brought significant improvement in 20 patients
with generalised/segmental dystonia during the 3-month follow-up (Kupsch et al. 2006)
while another controlled study showed that DBS targeted at the pallidus also brought
significant improvement in 22 patients with primary generalised dystonia in a double-blind
evaluation with and without stimulation during the 3-month follow-up (Vidailhet et al. 2006).
31
3.4 Musician’s Dystonia
Musical performance at a professional level is one of the most demanding cognitive and
sensorimotor activities, and this statement is supported by a plethora of studies showing the
structural and functional differences between musicians and non-musicians. (see Münte et
al. 2002 for a review; ex. Gaser and Schlaug 2003; Bengtsson et al. 2005; Schlaug 2009).
Nevertheless, the structural and functional changes brought by music-making to the brain are
not always as beneficial as they should be – especially if we take musician’s dystonia as a
case of maladaptive plasticity related to music-making.
Musician’s dystonia (MD), also known as musician’s cramp, is a task-specific movement
disorder which presents itself as a painless muscular incoordination or loss of voluntary
motor control of extensively trained movements while a musician is playing the instrument
(Altenmüller 2003). The prevalence of professional musicians suffering from MD is
approximately 0.5 – 1%, making it one of the most serious problems in the field of musician’s
medicine (Frucht 2004). It is highly disabling and about half of the patients suffering from
MD are forced to terminate their musical careers (Schuele et al. 2004). The first record of
MD dated back to Robert Schumann’s diaries in the 1830’s (Altenmüller, 2006), and the
story of the famous pianist Leon Fleisher has brought MD to the public’s and the medical
professional’s attention.
Figure 3.3
Typical dystonic postures in (clockwise from top left):
pianist, violinist, brass player (embouchure dystonia) and flutist
32
3.4.1. Etiology
As a form of FHD, the etiology of MD is still unclear. Nevertheless the current view is that
FHD is a multifactorial condition in which multiple genes, along with several environmental
risk factors interact in a network and contribute to the formation of the disorder (TorresRussotto et al. 2008; Altenmüller and Jabusch 2010).
External and internal factors may affect the general predisposition of a musician and interact
with each other (Figure 3.4). The factors include: genetic factors, the “workload” required for
the musical performance, psychological factors and trauma. To what degree each single
factor influences this multifactorial network is difficult to quantify and may differ between
subgroups of musicians.
Figure 3.4
The possible interplay between predisposition and intrinsic and extrinsic triggering factors in the manifestation
of musician’s dystonia (reproduced from Jabusch and Altenmüller 2006)
33
Genetic Factors
A study investigating genetic abnormalities in MD found that a GAG deletion of the DYT1
gene, which contributes to generalised dystonia, is not common among MD patients
(Friedman et al. 2000). This is not surprising since the generalised DYT1 dystonia differs
from MD in many aspects, including body distribution, onset age and task-specificity. In
recent years, there is emerging evidence showing that genetic factors may play an important
role in MD (Schmidt et al. 2006; Schmidt et al. 2009), and the endophenotypic traits are
demonstrated by the presence of other upper limb focal task-specific dystonia in family
members of these patients (Schmidt et al. 2006). In a more recent study by Schmidt and his
colleagues (2011), the results further support the genetic contribution to MD with a broad
individual and familial phenotypic spectrum consisting of MD, other dystonias and even
other, non-dystonic movement disorders. In terms of the effect of gender, demographic data
demonstrates that male musicians have a higher risk of developing MD compared to female
musicians (Lederman 1991; Lim and Altenmüller 2003; Jabusch et al. 2006).
“Workload” required for the musical performance
In order to meet the high musical standard set for professional performance, musicians are
used to intensive use of a particular body part for complex movement production to achieve
the sensorimotor precision needed – both spatially and temporally. In classical music, there is
an even higher demand for such precision, and this interestingly corresponds to the fact that
the majority of musicians suffering from MD are classical musicians (Jabusch and
Altenmüller 2006; Altenmüller and Jabusch 2010), and of these most are solo keyboard and
string instrumentalists/ keyboard and string soloists. In a study (Conti et al. 2008), a total of
960 musicians with focal dystonia were reviewed and characterized by the phenomenology
and pattern of involvement in each class of musical instruments. This study showed that the
pattern of involvement seems related to the specific technical demands of the musical
instruments on the hand and individual fingers involved. The importance of overtraining
precise, repetitive movement in contribution to FHD has been addressed in the previous
section, and classical music training heavily involves long-term practise of the
abovementioned movements. Abnormal (overlapped) finger representations in the
somatosensory cortex of the affected hand of MD patients have also been reported (Elbert et
al. 1998), and this further supports the hypothesis that that extensive practise might
contribute to MD.
34
Psychological Factors
Studies focusing on the psychological aspects of MD suggest that compared to healthy
musicians, musicians suffering from MD have higher levels of anxiety and perfectionism,
which precedes the onset of MD symptoms (Jabusch et al. 2004; Altenmüller and Jabusch
2009). The culture of music-making is very specific, and this could reinforce an extremely
strict system of reward and punishment, especially for classical musicians who have to be
scrutinised by the performers themselves and by the audience. This reinforcement may have
caused a stronger motor memory consolidation in instrumental playing than in other motor
activities, thus might play a role in the pathogenesis of MD (Altenmüller and Jabusch 2009).
Trauma
The role of both physical and psychological trauma has been discussed in several studies
(Charness et al. 1996; Frucht et al. 2000). However it has not been systematically studied so
far.
3.4.2. Pathophysiology of Musician’s Dystonia
Classified as a form of FHD, MD is often discussed under the pathophysiological framework
of FHD, which covers the loss of inhibition, sensory dysfunction and derangement of
plasticity (see section 3.3.3) and the interactions between these abnormalities.
There have been a few studies focusing on the pathophysiology of MD since 2010, and more
and more neuroimaging studies are becoming involved in the investigation: a few functional
magnetic resonance imaging (fMRI) studies on MD (embouchure dystonia patients,
Haslinger et al. 2010) and guitarists with focal hand dystonia (Kadota et al. 2010) have
revealed increased sensorimotor cortex activation and reduced thalamic and basal ganglia
activation; two exciting electroencephalography (EEG) studies (Ruiz et al. 2009; Ruiz et al.
2011) demonstrated that: (1) in a Go/NoGo paradigm, pianists suffering from MD had
reduced movement-related cortical potentials over the sensorimotor areas and reduced phase
synchronization between the SMA, the PMA and the sensorimotor area. (2) in errormonitoring, MD patients elicit larger beta oscillations and error-related negativity before
overt errors and altered phase synchronization. It is also worth mentioning that although the
role of cerebellum in dystonia has always been debated, a recent study (Lee et al. 2013) has
shown that the sensory dysfunction in MD might arise from altered forward model prediction,
which, it has been suggested, are computed within the cerebellum (Wolpert et al. 1998).
35
3.4.3. Treatment of Musician’s Dystonia
As mentioned in the section about treatment of dystonia, it is a challenge to assess the
appropriate therapeutic intervention, and this challenge is definitely even greater for MD due
to the task-specificity and the (often) subtle symptoms. It also requires a vast accumulation of
knowledge and experience related to the fine motor control in musical performance.
The commonly adopted therapeutic options for treating MD include pharmacological
treatment, BoNT injection, ergonomic modifications and sensorimotor retraining (Byl et al.
2000; Altenmüller 2003; Boullet 2003; Schuele et al. 2005; Candia et al. 2003).
Pharmacological treatment includes anticholinergic drugs that influence the
neurotransmission in the BG. Trihexyphenidyl, baclofen, primidone or phenytoin are
occasionally helpful (Chang and Frucht 2013). Unfortunately, despite being a helpful drug
for approximately 1/3 of the MD patients who showed symptoms in their limbs (Jabusch et
al. 2005), long-term treatment with trihexyphenidyl is not desirable according to some
patients because it induces side-effects such as memory impairment and would affect
performance quality. Local BoNT injection is widely adopted, unfortunately it only provides
temporary symptomatic relief. The best outcome of BoNT injection is shown in patients with
primary dystonic movements clearly distinguishable from secondary compensatory
movements (Jabusch and Altenmüller 2006), and patients who have limited demand on
lateral finger movement, such as guitarists and woodwind players (Jabusch et al. 2005),
therefore it is also recommended to the keyboard players suffering from MD to change their
repertoire to pieces that do not require a large hand span or much lateral finger movement.
Ergonomic modifications employ various immobilization apparatus such as a splint to
constrain/prevent dystonic movements, especially in fingers (Jabusch et al. 2005). Finally,
sensory re-training for MD includes constraint-induced training, immobilization, learningbased sensorimotor retraining, pedagogical retraining at the instrument and self-guided
exercises on the instrument (Jabusch et al. 2005; Altenmüller et al. 2010). The idea behind
sensory re-training is based on the hypothesis that MD is due to the maladaptive plasticity
and by working with the re-training programme, the abnormal somatotopic hand
representations can be restored. Nevertheless, among all the treatments sensory retraining is
the most time-consuming option, and the outcomes have been reported as heterogeneous (Byl
et al. 2000; Boullet 2003; Candia et al. 2003; Jabusch et al. 2005). However, Jabusch and
Altenmüller (2006) have emphasised the importance of behavioural aspects in all treatment
approaches, and suggest that it should at least be an adjunct.
36
4
Manuscript 1
Altered Sensory Feedbacks in Pianist's Dystonia:
the altered auditory feedback paradigm and the glove effect
Authors
Cheng, F. P.-H., Großbach, M. and Altenmüller, E.O.
Institute of Music Physiology and Musicians' Medicine, Hanover University of Music,
Drama, and Media, Hannover, Germany
Keywords
musician's dystonia, altered auditory feedback, glove effect, sensory trick, scale paradigm,
sensorimotor integration
Address for Correspondence:
Prof. Dr. Eckart Altenmüller
Institute of Music Physiology and Musicians’ Medicine
Hanover University of Music, Drama, and Media
Emmichplatz 1
30175 Hannover
Phone 00495113100552
Fax 0049 5113100557
Email [email protected]
37
Abstract
Background: This study investigates the effect of altered auditory feedback (AAF) in
musician's dystonia (MD) and discusses whether altered auditory feedback can be considered
as a sensory trick in MD. Furthermore, the effect of AAF is compared with altered tactile
feedback, which can serve as a sensory trick in several other forms of focal dystonia.
Methods: The method is based on scale analysis (Jabusch et al. 2004). Experiment 1 employs
synchronization paradigm: 12 MD patients and 25 healthy pianists had to repeatedly play Cmajor scales in synchrony with a metronome on a MIDI-piano with 3 auditory feedback
conditions: 1. normal feedback; 2. no feedback; 3. constant delayed feedback. Experiment 2
employs synchronization-continuation paradigm: 12 MD patients and 12 healthy pianists had
to repeatedly play C-major scales i n two phases: first in synchrony with a metronome,
secondly continue the established tempo without the metronome. There are 4 experimental
conditions, among them 3 are the same altered auditory feedback as in Experiment 1 and 1 is
related to altered tactile sensory input. The coefficient of variation of inter-onset intervals of
the key depressions was calculated to evaluate fine motor control.
Results: In both experiments, the healthy controls and the patients behaved very similarly.
There is no difference in the regularity of playing between the two groups under any
condition, and neither did AAF nor did altered tactile feedback hav e a beneficial effect on
patients’ fine motor control.
Conclusions: The results of the two experiments suggest that in the context of our
experimental designs, AAF and altered tactile feedback play a minor role in motor
coordination in patients with musicians' dystonia. We propose that altered auditory and tactile
feedback do not serve as effective sensory tricks and may not temporarily reduce the
symptoms of patients suffering from MD in this experimental context.
38
Introduction
Dystonia in pianists belongs to a group of dystonic movement disorders termed focal hand
dystonias (Chen and Hallett 1998). It is characterized by the degradation of voluntary control
of highly skilled movement patterns involved in piano playing. The condition frequently
results in co-contraction of wrist flexors and extensors and in involuntary curling, or
extending of digits, thus rendering fast movements involved for example in scale playing
irregular (Jabusch et al. 2004). It is known that focal hand dystonia involves several sensory
abnormalities, such as reduced two-point discrimination thresholds, reduced graphaesthesia
(Byl et al. 1996), and an impairment of the thermal detection thresholds (Suttrup et al. 2011).
Furthermore temporal judgment of somatosensory and auditory stimuli has been shown to be
altered in musicians suffering from dystonia (Lim et al. 2003). On the other hand, cutaneous
stimuli may reduce the severity of motor symptoms in some forms of focal dystonia. This
phenomenon is termed sensory trick. Studies into the “geste antagoniste”, a sensory trick
reducing severity of Torticollis, (a focal dystonia causing involuntary movements of the
muscles of neck and shoulder) suggested that successful sensory tricks can be regarded as
perceptual dysbalance, induce increased activation of the parietal cortex and together with the
frontal cortex, mediates distinct sensorimotor transformations that can help with correcting
the long-term dystonic posture. Accordingly, successful sensory tricks should be regarded as
a complex dynamic mechanism that corrects the perceptual dysbalance of the abnormally
defined posture (Naumann et al. 2000; Schramm et al. 2004). In task-specific focal dystonia,
sensory stimuli like wearing a latex glove may also reduce the severity of motor symptoms in
some forms of focal dystonia (Jabusch et al. 2011).
Based on the models proposed by the previous sensory trick studies, the present study aimed
at investigating the effect of altered auditory feedback (AAF) on MD under two widely used
paradigms for studying motor behaviour: (1) synchronization paradigm; (2) synchronizationcontinuation paradigm. The motivation for this study came from anecdotal reports of organ
players suffering from hand dystonia who reported a marked improvement of the motor
symptoms when playing on a pipe organ with delayed sound production after the key stroke
due to mechanical coupling of the keyboard and the organ pipes. Such observation was
valuable for the movement disorders research, yet the possible influence of altered auditory
feedback and altered somatosensory feedback on the fine motor control in MD had never
been investigated. Considering the delayed auditory feedback in these reports, it is well
known that the extensive training of professional musicians leads to plastic adaptations of
neural networks involved in the demanding temporal-spatial control of overtrained
movements (Bangert et al. 2006.; Zatorre et al. 2007), and it has been shown that AAF has a
39
great influence on the motor control in music performance of healthy musicians (Pfordresher
2006). Furthermore, it has been shown that altered auditory feedback can induce
improvement in speech in some movement disorders and motor speech disorders such as
stuttering, dysarthria and Parkinson’s disease (Alm 2004; Gentil 1993; Downie et al. 1981).
Based on the above reasons, we therefore hypothesized that AAF could account for the
anecdotal observations of the organ players and have an influence on the dystonic symptoms,
similar to the cutaneous sensory trick in torticollis patients.
Material and Methods
All procedures were approved by the ethics committee of Hannover Medical School and
participants gave written informed consent before data collection. All patients suffering from
MD were recruited from the outpatient clinic of the Institute of Music Physiology and
Musicians' Medicine of the Hannover University of Music, Drama and Media. They
underwent complete neurological examination and were diagnosed by one of the authors,
who is a neurologist and movement disorders specialist (EA). All other neurological and
health issues were excluded.
Experiment 1: Synchronization Study
Participants
12 professional pianists (8 males, 4 females, mean age=44.5, SD=9.6, mean accumulated
practice time=42086 hours, SD=25040) suffering from right hand MD and 25 healthy
professional pianists (13 males, 12 females, mean age=25.8 years old, SD=3.93, mean
accumulated practice time=25075 hours, SD=10754) participated in this experiment.
Combined two one-sided t-tests (TOST, Robinson & Froese 2004) shows that the two groups
are not equivalent with regard of their accumulated practice hours (p=0.92). According to the
Edinburgh inventory (Oldfield 1971), all the patients were right handed. 24 of the healthy
professional pianists were right handed and 1 was left handed.
Procedure
The method is based on Scale Analysis (Jabusch et al. 2004). Subjects were instructed to
repeatedly play 2 octaves of C major scales (from C4 to C6) in legato-style at a tempo of 80
beats per minute with 4 notes per beat (inter-onset intervals = 187.5 ms) in both upward and
downward directions as accurately as possible on a MIDI digital piano (Wersi Digital Piano
CT2) with their right hand only. There were 3 conditions for different types of auditory
feedback: 1. normal feedback (NORMAL), in which the auditory feedback occurred
40
simultaneously with the key depression; 2. no feedback (MUTE), in which no auditory
feedback is produced with the key depression; 3. fixed delayed feedback of 200 ms
(DELAY200), in which the auditory feedback occurred 200 ms after the key depression. The
selection of delay duration was meant to mimick the delayed auditory feedback of a pipe
organ in a resonant space. For each condition, the participant had to play at least 25 times of
complete upward and downward scales. The order of the conditions was randomized, and all
playing was synchronized to a real metronome placed on the digital piano (Wittner
metronome QM2 taktell). In DELAY200, subjects were explicitly instructed to synchronize
the piano sound to the metronome, not the movement. The onset and the offset time of each
key depression was recorded (measured in milliseconds, start of the program is defined as 0
ms). MIDI recording, as well as manipulation for the conditions MUTE and DELAY, were
done using a custom-made C program which acquired and (where applicable) manipulated
the MIDI events coming from the MIDI piano. Sound was played back to subjects via the
computer sound chip and two studio monitor speakers (Yamaha MSP 5) placed
approximately 1 m in front of the subjects, 150 centimeters apart.
Data Analysis
For each condition, as a measure of evenness of piano playing (which is required in
professional pianists), the regularity of timing of successive keystrokes (termed inter-onset
intervals, abbreviated as IOIs) was calculated from at least 20 sets of complete scales, except
for the last IOI of every scale because it was frequently elongated according to the pianist's
expressive playing. The coefficients of variation (CVs) were calculated to indicate the
̄x
)
, where
s
is
is the mean of the measured IOIs and
n
is
irregularity of timing of the scale playing. The CV is defined as:
the standard deviation of the measured IOIs,
(
1 s
*
ĉ v = 1+
4n ̄x
the number of scales a participant played in a given condition (Sokal & Rohlf 1995) and with
this de finition the term (1+1/4n) approaches 1 asymptotically with increasing
n
. The IOI
CVs were computed for upward and downward scales individually since these are two
different motor patterns. Finally the IOI CVs for all the patients and participants under all
types of auditory feedback and for both upward and downward directions of scale playing
were analyzed with ANOVA to detect the main effect of group and condition. The within
factors are playing direction (with levels "up" and "down”) and types of auditory feedback
(with levels "NORMAL", "MUTE" and "DELAY200"); the between factor is group (with
levels "patient" and "control"). The means of IOIs for both playing directions under different
conditions have been reported as well. All analyses were done using R (version 2.15.2; R
Core Team 2012) scripts in RStudio (version 0.97.551; Rstudio 2013). Multiple comparisons
were corrected using Holm's (1979) method.
41
Results of Experiment 1
The target dependent variable in this study was the coefficient of variation of inter-onset
intervals, being an objective measure of playing regularity in pianists with MD. To determine
differences in playing speed, the inter-onset intervals were analyzed as well: Regarding to the
mean IOIs, a main effect of auditory feedback condition (F(2,70)=8.832, Greenhouse-Geisser
epsilon=0.740, p < 0.001) was found but no effect of group (F(1,35)=0.350, p>0.05) or scale
playing direction (F(1,35)=2.445, p=0.127) and no significant interactions were found
(F(2,70)=2.498, p>0.05). (See Figure 1). The results of the healthy group during DELAY200
condition were untypical comparing to most reports of delayed auditory feedback. In our
results of Experiment 1, the healthy group showed a decrease in mean IOIs (movement
speeding up) while in most reports the participants show increased IOIs (movement slowing
down). Possible explanations for this result are (1) as a strategy to cope with the delayed
auditory feedback, the participants played faster in order to “get ahead” of the delay (Gates et
al. 1974); (2) the effect of delayed auditory feedback on the timing of movement production
is related to both the phase of actual movement execution and cognitive planning. It has been
suggested that when delayed auditory feedback co-occurs with the downswing phase of
movement execution, on a cognitive planning level, auditory information compliments the
regulation of movement, and thus facilitates the approach to the goal, which may shorten the
IOIs (Pfordresher and Dalla Bella, 2011). This effect might had played a role in our
Experiment 1.
Figure 1
Interaction plot of mean IOI’s for Experiment 1.
Shown are the estimated mean IOIs (ms) conditional on group membership and auditory manipulation,
collapsed over playing direction. Error bars denote 95% confidence intervals.
42
Regarding to the IOI CVs, there was a main effect of group (F(1,35)=16.427, p<0.001) and
the patient group generally showed higher IOI CVs than the healthy controls. A main effect
of feedback condition was also found (F(2,70)=34.178, Greenhouse-Geisser epsilon=0.676,
p<0.001), but no significant interactions were found (Figure 2). Both groups had increased
IOI CVs for the DELAY200 condition, showing that DELAY200 induced unevenness in
scale playing (pairwise t tests: NORMAL-MUTE: p>0.05; NORMAL-DELAY200: p<0.001;
DELAY200-MUTE: p<0.001), meaning that they did not benefit from these two auditory
manipulations in this synchronization paradigm. The patient group showed a very weak
tendency towards higher IOI CVs in upward scale playing (Fig. 2; F(1,35)=3.497, p=0.07).
This is possibly related to the task-specificity of focal hand dystonia revealed under different
motor patterns involved in playing directions. It should be mentioned, that the upwards scales
are more complex due to the thumb-under passage, requiring a complex anticipatory
coordination maneuver of thumb, remaining four fingers and the wrist.
Figure 2
Interaction plot of IOI CVs for Experiment 1. Error bars denote 95% confidence intervals.
Discussion of Experiment 1
The results of Experiment 1 showed that neither did the complete deprivation of auditory
feedback nor did a constantly delayed auditory feedback of 200 ms serve as a successful
sensory trick, which is against our hypothesis. Experiment 1 also showed an effect of
auditory feedback condition on mean IOIs in both groups. However, the two groups of
participants are very different in terms of their age and their years of accumulated hours of
practice. Pianists suffering from MD are generally older than the healthy controls. In
Experiment 2, we had tried our best to reduce this discrepancy.
43
Experiment 2: Synchronization-Continuation Study
Following Experiment 1, in which deprivation of auditory feedback and delayed auditory
feedback did not serve as a sensory trick that could improve the fine motor control in MD,
Experiment 2 was carried out. One problem inherent to playing scales with delayed feedback
to a metronome is probably the higher task difficulty in this condition. Anticipating the
auditory feedback and executing the key presses 200 ms in advance during scale playing in
order to exactly synchronize with the metronome proved to be difficult for both healthy
pianists and pianists suffering from MD, and this might have shifted the pianist's attention
away from the scale playing towards the out-of-phase synchronization of movements to the
metronome, leading to a different neural process that is required to pace the movement
according to an external stimulus (Serrien 2008). To circumvent this problem, in experiment
2 we applied the synchronization-continuation paradigm, and reduced the delay to 90ms since
this would reduce the degree of asynchrony involved in Experiment 1.
Participants
12 professional pianists suffering from right hand MD (9 males, 3 females, mean age=41,
SD=10.4, mean accumulated practice time=37593 hours, SD=11199) and 12 healthy
professional pianists (5 males, 7 females, mean age=33.3 years old, SD=11.6, mean
accumulated practice time=35495 hours, SD = 24317) participated in this experiment. TOST
suggested that the two groups were not equivalent with regard of their accumulated practice
hours (p = 0.356). All the pianists suffering from MD were right handed. 11 of the healthy
controls were right handed and 1 was left handed, according to the Edinburgh inventory
(Oldfield 1971). 2 of the pianists suffering from right hand MD had participated in
Experiment 1. None of the healthy pianists had participated in experiment 1.
Procedure
Similar to Experiment 1, the method of Experiment 2 is also based on Scale Analysis, but the
conditions are designed according to the synchronization-continuation paradigm (Stevens
1886; Finney and Warren, 2002; Pfordresher and Palmer, 2002), and one more condition,
which is the altered tactile feedback condition, was included. The synchronizationcontinuation paradigm is widely used in studies of temporal coordination between actions and
sound. During the experiment, the participants were instructed to repeatedly play 2 octaves of
C major scales (from C4 to C6) with right hand in legato-style at a tempo of 80 beats per
minute with sixteenth notes (4 notes per beat, inter-onset interval = 187.5 ms) in either
upward or downward directions as accurate as possible on the same digital piano used in
Experiment 1. The first phase of each condition was the synchronization part, the participant
44
had to play 10 sets of scales according to a metronome click sound generated by the computer
and played through 2 speakers (Yamaha MSP 5). The second phase of each condition was the
continuation part and the participant had to maintain the same way and same tempo of
playing for at least 20 sets of complete and error-free scales in the absence of metronome
sound. It was in the continuation part that the altered auditory feedback (if any) was
employed. Similar to experiment 1, there were 3 different types of auditory feedback used in
the continuation part: ( 1 ) normal auditory feedback (NORMAL); (2) muted feedback
(MUTE); (3) with fixed delayed feedback of 90 ms (DELAY90). In the (4) tactile condition,
auditory feedback was as in NORMAL but subjects wore a latex glove (GLOVE) on their
playing hand throughout both the synchronization and continuation phases. The order of the
conditions was randomized in 2 blocks. In one block the participants played upward scales
only, and in the other block they played downward scales only. The order of the two blocks
was also randomized. Between the blocks the participants were instructed to take a 2 minutes
rest. The metronome sound onset time in the synchronization phase and the onset and the
offset time of each key depression were recorded (measured in milliseconds, start of the
program is defined as 0 ms). Other than that, apparatus was the same as in Experiment 1.
Data Analysis
Both the synchronization and the continuation parts of each condition were analysed. The
first scale of the continuation phase was discarded from the analysis because of the common
increase in unevenness among the participants. Similar to Experiment 1, the IOI CVs from at
least 20 sets of complete, error-free scales were calculated to indicate the irregularity of
timing of the participants in each condition. To determine how well subjects synchronized
with the metronome, we ran a within-between ANOVA on the mean temporal deviation of
key presses from the metronome tick [between factor: group (levels “patient” and “control”);
within-factors: treatment (levels “NORMAL”, “MUTE”, “DELAY90”, “GLOVE”) and
playing direction (levels “up”, “down”)]. On the IOI CVs, again a mixed effects ANOVA
was calculated (factors and levels same as just mentioned). After the results suggested that
there was no effect of playing direction, a between-within Ss ANOVA was run on the mean
IOI CVs collapsed across playing directions to increase possible group effects [between
effect: group (levels “control”, “patient”), within effect: treatment (levels “NORMAL”,
“MUTE”, “DELAY90”, “GLOVE”)]. All analyses were done using R (version 2.15.2; R
Core Team 2012) scripts in RStudio (version 0.97.551; Rstudio 2013).
Results of Experiment 2
For the synchronization phase, both groups display negative asynchrony (keypress was in
advance of the metronome; Repp 1999). No significant main effect of group was found in this
phase, suggesting that there is no difference between the patient and control group in terms of
45
synchronization (F(1,22)=2.679, p>0.05; Figure 3), showing that both groups had similar
degree of synchronization to the metronome. There were also no statistically signi ficant
effects of sensory feedback (F(3,66)=0.877, Greenhouse-Geisser epsilon=0.513,p>0.05) and
playing direction (F(1,22)=2.807, p>0.05).
Figure 3
Mean of the mean deviations from the metronome in the synchronization phase in Experiment 2. Shown are the
estimated mean IOIs (ms) conditional on group membership and auditory manipulation, collapsed over playing
directions. Error bars denote 95% confidence intervals.
For the continuation phase, regarding to the mean IOI’s, no main effects and no significant
interactions were found (group: F(1,22)=1.726, p>0.05; sensory feedback: F(3,66)=3.069,
Greenhouse-Geisser epsilon=0.529, p>0.05; playing direction: F(1,22)=0.001, p>0.05; group
x sensory feedback: F(3,66)=0.772, p>0.05). (Figure 4).
46
Figure 4
Interaction plot of mean IOIs for Experiment 2 during continuation phase.
Details as in Fig. 1. Error bars denote 95% confidence intervals.
Similar to Experiment 1, with regard to the IOI CVs, a significant main effect was found for
sensory feedback (F(3,66)=93.026, Greenhouse-Geisser epsilon=0.385, p<0.001), possibly
attributable to a significantly deteriorated motor performance for DELAY condition during
the continuation phase (pairwise t tests: NORMAL-MUTE: p>0.05; NORMAL-DELAY90:
p<<0.05; NORMAL-GLOVE: p>0.05; Figure 5). No significant interactions were found
(F(3,66)=1.65, p>0.05). Individual mean IOI CVs of all the patients during the continuation
phase under different conditions are detailed in Table 1, with the IOI CVs of upward and
downward directions averaged. From the table, one can see that only 4 patients who have less
severe symptoms had slightly improved motor control under MUTE and only 1 patient had
improved motor control under DELAY90 condition, while 5 patients had slightly improved
motor control under GLOVE condition. Improved IOI CVs are marked in bold and italic
fonts. Paired and one-sided t-tests of the IOI CVs calculated from each scale run were used to
verify if the patient had signi ficantly improved motor control under certain condition. For
each patient, the NORMAL condition is tested against other altered sensory feedback
conditions. The alternative hypothesis is that the true difference between the means is greater
than 0. Therefore in Table 1, the altered sensory feedback conditions that show signi ficantly
reduced IOI CVs are the ones having p<0.05 and are underlined.
47
Figure 5
Interaction plot of IOI CVs for the continuation phase of Experiment 2.
Error bars denote 95% confidence intervals.
Patient ID
NORMAL
MUTE
DELAY90
GLOVE
p01
0.63
0.635
1.245
0.595
p02
0.29
0.275
1.005
0.335
p03
0.315
0.485
0.855
0.32
p04
0.435
0.465
0.955
0.49
p05
0.445
0.61
1
0.45
p06
0.315
0.28
0.785
0.285
p07
0.57
0.63
0.92
0.61
p08
0.495
0.36
0.895
0.355
p09
0.62
0.825
1.445
0.57
p10
0.335
0.34
0.84
0.315
p11
0.275
0.255
0.21
0.27
p12
0.445
0.5
0.715
0.39
Table 1
Individual mean IOI CVs of all the patients in Experiment 2.
The conditions in which the patient showed less IOI CVs are marked with bold and italic fonts, and are
underlined if p<0.05 according to the paired and one-sided t-tests.
48
Compared to Experiment 1, both the healthy controls and the patients had markedly increased
IOI CVs for the delay condition. This might be due to the effects of combined delayed
auditory feedback plus pitch alteration are smaller than either kind of alteration on its own
(Pfordresher 2003). In Experiment 1, the duration of delay was 200 ms, which was longer
than the theoretical IOI of keypresses (187.5 ms), induced pitch shift relative to the keypress
as well; whereas in Experiment 2, the duration of delay was 90 ms, which was shorter than
the theoretical IOI of keypresses, did not induce such pitch shift. Interestingly, in Experiment
2, there was no main effect of group while in Experiment 1, there was significant main effect
of group. This stark contrast might be due to the different durations of the delay (200 ms for
Experiment 1 and 90 ms for Experiment 2) and the different nature of the tasks
(synchronization in Experiment 1 and continuation phase in Experiment 2). Playing with
delayed auditory feedback in the continuation phase was much more difficult than in the
synchronization phase, the healthy subjects showed significantly deteriorated fine motor
control as well therefore there was no clear main effect of group.
Discussion
In both Experiment 1 and Experiment 2, we found no difference between the behaviour of
healthy controls and patients. None of the AAF that we employed (either MUTE or DELAY
of 200 ms and 90 ms), and nor did the altered tactile feedback (GLOVE) improve the fine
motor control of pianists suffering from MD. Taken together, the results are against our
hypothesis, which assumed that the AAF or altered tactile feedback might serve as forms of
successful sensory trick.
To the best of our knowledge, the only study that tested the role of auditory feedback in
dystonia is a case study (Kojovic et al. 2012) in which a patient with generalized DYT1
dystonia showed dramatically improved symptoms while playing electric piano with auditory
feedback. This improvement was reduced while the auditory feedback was masked but still
noticeable. However, the reduction of dystonic symptoms in this case is considered different
from typical sensory tricks, and is proposed to be more similar to paradoxical improvement
(Fahn 1989). What’s more, primary generalized dystonia and focal dystonia differ in many
respects, including the thresholds of sensory spatial discrimination (Molloy et al. 2003).
AAF has been extensively studied in speech and music performance related research. It has
been shown that stuttering frequency can be significantly decreased by masking the auditory
feedback (e.g. MacCulloch et al. 1970) or by delayed auditory feedback (e.g. Kalinowski et
al. 1996), and delayed auditory feedback may serve as a treatment (Van Borsel et al. 2003).
49
In music performance, auditory feedback has been shown to play a crucial role in the selfmonitoring of music performance. It is shown that AAF can profoundly disrupt the
performance of healthy professional musicians, and asynchronies between auditory feedback
and actions primarily disrupt the timing of actions (Pfordresher 2006). In the present study,
AAF, especially delayed auditory feedback, disrupted the performance of both healthy
pianists and pianists suffering from MD.
The MUTE condition can be seen as a task which directs the participants’ attention towards
their own movement. Theoretically speaking, the deprivation of auditory feedback would deautomatize the extensively trained auditory-motor coupling of expert musicians, thus recruit
the structures outside the basal ganglia – supplementary motor area (SMA) system, such as
the premotor cortex, which can only provide internally cued complex motor sequence during
de-automatization (Alm 2004). Nevertheless, only a few patients who had less severe
symptoms participated in the current study showed mild benefit from such attentional shift,
suggesting that the abnormal neural network involved in musician’s dystonia may not be
normalized by this de-automatization, and it is reasonable to speculate that the more severe
MD is more closely linked to deficient procedural memory, as is the case for several other
movement disorders (Doyon 2008). Although it has been shown that the functional cortical
network in focal hand dystonia patients is impaired (Jin et al., 2011), the deprivation of
auditory feedback in the long-trained coupling of sensorimotor cortical areas did not act as
successful sensory trick for our patients. Instead, it has even been shown to have a
detrimental effect on MD patient’s fine motor control in the present study. The possible
explanation for this finding is that playing scales under the MUTE condition relies heavily on
an internal model that does not require auditory feedback, and the internal model has been
shown to be impaired in MD (Herrojo Ruiz et al. 2009; Herrojo Ruiz et al. 2011; Lee et al.
2013).
The DELAY condition is essentially a task which manipulates the effect produced by
participants’ movements, which is similar to the studies that investigated the influence of the
performer’s focus of attention, which suggested that directing one’s attention to the effects of
the movements (external focus) involves different motor control processes than directing
one’s attention to one's own movements (internal focus) (McNevin et al. 2002). In case of
movement disorders, it has been shown that patients with Parkinson’s disease and a fall
history can improve their balance with the adoption of an external focus (Landers et al.
2005). It should be noted that the sensory trick was once considered as a manoeuvre for distracting patients’ attention (Abbruzzese and Berardelli, 2003). Nevertheless, in the current
study, it is also shown that the manipulation of an external focus deteriorates the motor output
50
and does not bring any benefit to the patients the way a successful sensory trick may do. It is
interesting to note that the patients’ playing was still affected by the manipulation of the
external focus of attention similar to the healthy controls, implying the action and sound
production are still strongly coupled in MD patients.
One of the studies that put an emphasis on the altered tactile feedback is a study carried out
by Jabusch and colleages (2011). Nevertheless, in this study, the authors addressed a different
research question which aimed at the potential association between tactile sensory trick
phenomenon (“glove effect” in this study) and the outcome after consequent treatment with
botulinum toxin and/or pedagogical re-training. Furthermore, in this previous study, only
19% of patients showed significant improvement of fine motor control through wearing a
glove in this study, and the patients who participated in this previous study had more severe
symptoms (with median of standard deviations of inter-onset intervals of scale playing = 20.0
ms) than our patients (median of standard deviations of inter-onset intervals of scale playing
= 14.76 ms). In the present study, we have smaller samples sizes (12 patients in both
experiments) than the previous study. Both differences (degree of severity and sample size)
could explain why in the current study there were no effects of glove on a group level. It
should be mentioned, however, in the present study several individuals suffering from focal
dystonia benefitted from glove condition. This points toward the heterogeneity in neural
and/or behavioural organisation of musician’s dystonia.
Behavioural studies on the sensory functions in dystonia is gaining its importance in light of
providing effective strategies for recovery and understanding the underlying mechanisms
(Tinazzi et al. 2009). In musician’s dystonia, although it has been shown that patients have
deficits in temporal judgment, it was not clear how this sensory deficit can affect their
playing ability under a disrupted sensory feedback network. Although the starting point of
this study was the reports related to pipe organs having delayed auditory feedback, the
present study provides evidence showing that the defected sensory network could not be
normalized by the altered auditory feedback conditions used in this experiment or altered
tactile feedback such as wearing the glove. We hope that these results can contribute into
further research in the sensory aspects of focal task-specific dystonia and help us to provide
the patients with correct information and guide the patients with the most efficient therapeutic
options.
Acknowledgements
We wish to thank Mr. Aguirre, Mr. Hagemann and Mr. Neubauer for programming the MIDI
recording and manipulation program and the reviewers for the constructive comments.
51
5
Manuscript 2
Sensory Feedback – Dependent Neural De-orchestration:
the effect of altered sensory feedback on Musician's Dystonia
Authors
Cheng, F. P.-H.1, Eddy, M.-L.1, Herrojo Ruiz, M2, Großbach, M1. and Altenmüller, E.O.1
1. Institute of Music Physiology and Musicians' Medicine, Hanover University of Music,
Drama, and Media, 30175 Hannover, Germany
2. Department of Neurology, Charité University of Medicine, 13353 Berlin, Germany.
Keywords
Pianist, EEG, altered auditory feedback, phase synchronisation, scale paradigm, sensorimotor
integration.
Address for Correspondence:
Prof. Dr. Eckart Altenmüller
Institute of Music Physiology and Musicians’ Medicine
Hanover University of Music, Drama, and Media
Emmichplatz 1
30175 Hannover
Phone 00495113100552
Fax 0049 5113100557
Email [email protected]
52
Abstract
Musician's dystonia (MD) is a task-specific movement disorder related to extensive expert
music performance training. Similar to other forms of focal dystonia, MD involves sensory
deficits and abnormal patterns of sensorimotor integration. The present study investigated the
impaired cortical sensorimotor network of pianists who suffer from MD by employing altered
auditory and tactile feedback during scale playing with multichannel EEG. The comparison
of EEG data in healthy pianists and pianists suffering from MD revealed a higher degree of
inter-regional phase synchronisation between the frontal and parietal regions and between the
temporal and central regions in the patient group and in conditions that are relevant to the
long-trained auditory-motor coupling (normal auditory feedback and complete deprivation of
auditory feedback), but such abnormalities are decreased in conditions with delayed auditory
feedback and altered tactile feedback. These findings support the hypothesis that the impaired
sensorimotor integration of MD patients is specific to the type of overtrained task that the
patients were trained for and can be modified with altered sensory feedback.
53
Introduction
Musician's Dystonia (MD) is a task-specific movement disorder that manifests itself as a
painless muscular incoordination or loss of voluntary control over extensively trained
movements while playing an instrument (Jankovic and Shale, 1989; Altenmüller 2003). MD
is often discussed under the pathophysiological framework of focal dystonia (FD), which
covers the loss of inhibition, sensory dysfunction, derangement of plasticity and the
interactions between these abnormalities that lead to abnormal motor planning at several
levels of the central nervous system (Quartarone and Hallett 2013).
Unlike most of the other forms of FD, MD is a disorder that involves abnormalities that are
partly induced by the training in expert music performance. In order to gain a better
understanding of the etiology of MD, it is therefore important to compare healthy musicians
with MD patients and relate the findings to adaptive and maladaptive neural plasticity that
may occur as a consequence of overtraining. This may impact sensory motor integration and
more specifically the auditory-motor interactions because they are a common feature of
expert music performance (Münte et al. 2002; Zatorre et al. 2007).
In EEG studies on MD patients, abnormal cortical activation patterns have been demonstrated
during the preparation, execution and inhibition of movement, especially in the beta band,
showing deficits in sensorimotor integration. Furthermore, in tasks requiring inhibition, MD
patients had significantly smaller cortical potentials and weaker power of beta oscillations
over the sensorimotor areas and reduced global phase synchronisation due to the weaker
phase synchronisation between the supplementary motor area (SMA), the premotor cortice
(PMA) and the sensorimotor area (Herrojo Ruiz et al. 2009). This was interpreted as a sign of
defective inhibition and lack of appropriate information transfer between areas linked to
retrieval of automated motor programs and areas linked to motor execution. In addition, with
respect to error-monitoring during piano playing, MD patients elicited larger post-error beta
band spectral power and showed altered patterns of phase synchronisation between the
posterior frontomedial cortex (pFMC) and lateral prefrontal cortex (Herrojo Ruiz et al. 2011),
again showing that the neural “orchestration” in the many motor related cortical areas is
deranged. These functional abnormalities in the fast neuronal interactions in EEG studies are
supplemented by fMRI studies during symptomatic and asymptomatic tasks, demonstrating
that MD patients had increased neuronal activation in bilateral primary sensorimotor cortices,
bilateral PMAs, and the ipsilateral PMA (Haslinger et al. 2010; Kadota et al. 2010).
Surprisingly, up to now this presumably impaired sensorimotor network in MD patients
54
during the execution of the symptomatic task has not been investigated under conditions of
altered sensory feedback. To this aim, the present study chooses one of the most explicit
methods of studying sensorimotor integration: the alteration of sensory feedback, in both the
auditory and tactile modalities, during keyboard performance. Our hypotheses are (1) the
degree of inter-regional phase synchronisation between the cortical regions involved in the
sensorimotor network is altered in MD patients, and (2) the patterns of such alteration are
dependent on the sensory feedback.
Materials and Methods
The ethics committee of Hannover Medical School approved all procedures and participants
gave written informed consent before data collection. All patients suffering from MD were
recruited from the outpatient clinic of the Institute for Music Physiology and Musicians'
Medicine of the Hannover University of Music, Drama and Media. They underwent complete
neurological examination and were diagnosed by one of the authors, who is a neurologist and
movement disorders specialist (EA). All other neurological and health issues were excluded.
Participants
9 healthy professional pianists (3 males, 6 females, mean age = 32.6 years old, SD = 9.8,
mean accumulated practice time = 33194 hours, SD = 24472) and 9 professional pianists
suffering from right hand MD (6 males, 3 females, mean age = 41.2, SD = 9.4, mean
accumulated practice time = 38235 hours, SD = 12709) participated in this experiment. 8 of
the healthy controls were right-handed and 1 was left-handed. All the pianists suffering from
MD were right-handed, according to the Edinburgh inventory (Oldfield 1971).
Stimulus Materials
The stimulus is based on Scale Analysis (Jabusch et al. 2004), which is an objective way to
evaluate the severity of MD in pianists by analysing the temporal evenness of scale playing.
During the experiment, the participants were instructed to repeatedly play 2 octaves of C
major scales (from C4 to C6) with right hand in legato-style at a tempo of 80 beats per minute
with sixteenth notes (4 notes per beat, inter-onset interval = 187.5 ms) in either upward or
downward directions as accurate as possible (Figure 1) under each condition.
Figure 1. Musical Stimuli
The fingerings 1-5 refer to thumb, index, middle, ring and little finger, respectively.
Downward scales are played with reversed fingering.
55
Experimental Design
Participants were comfortably seated at a digital piano (Wersi Digital Piano CT2) on an
adjustable chair with back support. The keyboard and the right hand of the participant were
covered with a paper board to prevent the participants from visually tracking the keyboard
and hand/finger movements. On the edge C4 and C6 keys, “start” and “stop” were marked so
the participants knew where to start the scale playing. Both the metronome and MIDI sounds
were generated by a computer synchronised to the other computer, which recorded the EEG,
and were both played through 2 speakers (Yamaha MSP 5) placed on the left and right side of
the digital piano.
The conditions are designed according to the synchronisation-continuation paradigm (Stevens
1886; Finney and Warren, 2002; Pfordresher and Palmer, 2002). The first phase of each
condition was the Synchronisation part: the participant had to play 10 sets of scales according
to a metronome click sound generated by the computer. The second phase of each condition
was the Continuation part and the participant had to maintain the same way and the same
tempo of playing for at least 20 sets of complete and error-free scales in the absence of
metronome. It was in the Continuation part that the altered auditory feedback (if any) was
employed. See Figure 2 for the scheme of the experimental paradigm.
Figure 2.
Scheme of the experimental Paradigm
56
3 different types of auditory feedback and 1 type of altered tactile feedback were used in the
Continuation part in 3 conditions:
(1) Normal auditory feedback x normal tactile feedback (Normal Condition);
(2) No auditory feedback x normal tactile feedback (Mute Condition);
(3) With fixed delayed auditory feedback of 90 ms x normal tactile feedback (Delay
Condition);
(4) Normal auditory feedback x altered tactile feedback (Glove Condition).
In (4) Glove condition, subjects wore a latex glove on their playing hand throughout both the
Synchronisation and Continuation phases.
The order of the conditions was randomized within the 2 blocks. In one block the participants
played upward scales only, and in the other block they played downward scales only. The
order of the two blocks was also randomized. Between the blocks the participants were
instructed to take a 2-minute rest with their eyes closed. During the 2-minute rest the EEG
was also recorded. The metronome onset time in the synchronisation phase and the onset and
the offset time of each key depression were recorded (measured in milliseconds, start of the
program is defined as 0 ms).
EEG recordings and Pre-processing
Continuous EEG was recorded from 22 electrodes placed over the scalp according to the
extended 10-20 system referenced to linked mastoids. Additionally, a left vertical
electrooculogram was recorded to monitor blinks and eye movements. Impedance was kept
under 5kΩ. Data were sampled at 250Hz; and lower cutoff was 0.05 Hz and the upper cutoff
was 40 Hz (software by NeuroScan Inc., Herndon, Va., USA). Note onsets and metronome
beats were automatically documented with markers in the continuous EEG file. EEGLAB
Matlab® Toolbox (Delorme and Makeig, v12.0.2.2) was used for visualisation, filtering and
artifact elimination. A high-pass filter of 0.5 Hz was applied to remove linear trends. The
EEG data were filtered between 1 to 40 Hz, average-referenced, cleaned of artefacts such as
blinks and eye movements (especially horizontal eye movements resulting from tracking the
direction of the hand while playing the scales) by rejecting related components identified
with the embedded independent component analysis (ICA) of EEGLAB. The data epochs
representing single scale-run (which includes 2 octaves) were time-locked to the onset of the
first key press of the scale-run (therefore C4 for upward scale-runs and C6 for downward
57
scale-runs) and were extracted from -100 to 2796 ms relative to the first note onset, resulting
in at least 38 artefact-free epochs for each condition for each participant. The baseline was set
at -100 to 0 ms relative to the first note onset.
Performance Data Analysis
Since the situations where altered feedback occurred were the interest of the present study,
the analyses focused on the Continuation parts of each condition. The first scale of the
Continuation phase was discarded from the analysis because of the common increase in
unevenness among the participants. All the time intervals between successive keystrokes
(termed inter-onset intervals, abbreviated as IOIs) were calculated from at least 19 sets of
complete, error-free upward and downward scales. For each participant, the coefficients of
variation (CVs) were calculated to indicate the evenness of piano playing (which is required
in professional pianists) of the scale playing for each condition. The CV is defined as:
(
)
1 s
ĉ *v = 1+
4n ̄x
, where s is the standard deviation of the measured IOIs, ̄x is the mean of the
measured IOIs and n is the number of scales a participant played in a given condition
(Sokal & Rohlf 1995) and with this definition the term (1+1/4n) approaches 1 asymptotically
with increasing n . Similarly to the EEG pre-processing analysis (see previous section), the
first scale of the Continuation phase was discarded from the performance analysis. On the IOI
CVs, a mixed effects within-between ANOVA was calculated [between factor: group (levels
“patient” and “control”); within-factors: treatment (levels “Normal”, “Mute”, “Delay90”,
“Glove”) and playing direction (levels “up”, “down”)]. After the results suggested that there
was no effect of playing direction, a between-within Ss ANOVA was run on the mean IOI
CVs combining both playing directions to increase possible group effects [between effect:
group (levels “control”, “patient”), within effect: treatment (levels “Normal”, “Mute”,
“Delay90”, “Glove”)]. All analyses were done using R (version 2.15.2; R Core Team 2012)
scripts in RStudio (version 0.97.551; Rstudio 2013). The behavioural data were already
reported as part of another manuscript dealing with the effect of altered sensory feedback in
MD (Cheng et al. 2013).
EEG Phase synchronisation Analysis
In order to investigate the dynamical interaction between oscillatory populations of different
recorded regions, bivariate phase synchronisation analysis (Lachaux et al., 1999; Pereda et
58
al., 2005) was performed to the EEG data. The transient phase relationships is emphasized in
the present study because unlike the spectral power analyses, it does not take the amplitude in
the oscillatory activities into the analyses and shows the functional coupling between the
oscillatory activities of underlying neuronal populations (Varela et al. 2001). The latter
phenomenon has also been shown to be abnormal in FD patients (Jin et al. 2011a; Jin et al.
2011b). A complex Morlet wavelet was used to extract time-frequency complex phases
φik(t,f), at an electrode i and epoch k, and amplitudes Aik(t, f) = |Wxik(t,f)| of the EEG signal
x(t). The constant η characterizes the family of wavelet functions in use and defines the
constant relation between the centre frequency and the bandwidth η = f/σf. A value η = 7 was
selected to provide a good compromise between high frequency resolution (σf = f/η) at low
frequencies and high time resolution (σt = η/4πf) at high frequencies. In order to analyse the
bivariate phase synchronisation, the strength of the phase coupling between two electrodes i
and j, at time t and with a centre frequency f was computed as
This index approaches 0 (1) for no (strict) phase relationship between the considered
electrode pair across the epochs. When averaged across pairs of electrodes, the index R ij
represents a measure of global synchronisation strength R. These indices were the basis of the
following statistical analysis (see below).
The calculations of the pairwise phase synchronisation were divided into ten regions of
interest (ROI; Figures 4-7, indicated by each of the shaded areas. T7 and T8 are considered to
be auditory-related regions and are thus combined into one region, which is ROI 7). The
criteria for ROI selection were based on a priori anatomical and functional knowledge and the
physiological evidence from the studies mentioned in the introduction. Phase synchronisation
activity in the beta band (13 – 30 Hz) was analysed due to its importance in long-range
synchronisation (Gail et al. 2004; Tallon-Baudry et al. 2001; Tallon-Baudry et al. 2004), in
normal function of the motor system (Engel and Fries, 2010) and in the pathophysiology of
several generalised movement disorders including FD (Kristeva et al. 2005; Kühn et al. 2008;
Jin et al. 2011a; Jin et al. 2011b).
Statistical Analysis
We were specifically interested in the between-group differences under each altered sensory
59
feedback condition. To this purpose, for the EEG data, we focused on comparing the phase
synchronisation indices between the healthy pianists and the MD patients under different
conditions. In each group the indices of phase synchronisation were averaged across 13-30
Hz and across the electrodes in each ROI. Next, in each ROI and for each time point within
the epoch, the averaged indices were analysed by means of nonparametric pairwise
permutation test across participants by computing 5000 permutations. The test statistic used
was the difference between sample means (MD – healthy). Differences were considered
significant if p<0.05 and the threshold value after Bonferroni correction would be 0.00056.
The global synchronisation strength R under each condition for each participant was
calculated, and a two-sample t-test was used to compare the overall phase synchronisation
between the two groups under each condition. Differences were considered significant if
p<0.05.
Results
Performance Analyses
With regard to the IOI CVs, a significant main effect was found for sensory feedback
(F(3,48)=69.10, Greenhouse-Geisser epsilon=0.62 , p<<0.001), attributable to a significantly
deteriorated motor performance for the Delay condition during the Continuation phase in
both groups (pairwise t tests: Normal-Mute: p = 0.99; Normal-Delay: p<<0.05; NormalGlove: p = 0.99). A trend of group effect (F(1,16) = 3.6, Greenhouse-Geisser epsilon=0.09,
p=0.07) but no significant interaction was found. The IOI CVs of each group under different
conditions can be found in Table 1, for the interaction plot of IOI CVs (see Figure 3).
Table 1
Descriptive Statistics of IOI CVs of all the healthy pianists (controls) and MD patients (patients)
60
Figure 3
Interaction plot of IOI CVs for the Continuation phase.
Error bars denote 95% confidence intervals.
61
EEG Phase synchronisation Analyses
Topographic phase synchronisation map for the comparison between the healthy and the MD
patients during Normal, Mute, Delay and Glove conditions are displayed in Fig 4, 5, 6 and 7.
Normal Condition
A significant increase in the global synchronisation strength was found in MD patients in the
Normal Condition (p = 0.04). For the between-group comparisons, the electrode pairs that
had a p-value under 0.05 in the index of phase synchronisation are between the left lateral
prefrontal areas and the medial frontal areas (ROI 1 and ROI 8, p = 0.0154) and the right
inferior parietal areas (ROI 1 and ROI 6, p = 0.0112), between the right prefrontal areas and
the left primary motor area (ROI 2 and ROI 3, p = 0.0314), the SMA (ROI 2 and ROI 9, p =
0.0442), and the right inferior parietal areas (ROI 2 and ROI 6, p = 0.024). The MD patients
had a higher degree of phase synchronisation between all the abovementioned pairs of
electrodes.
Figure 4
Topographic phase synchronisation map for the comparison between the healthy and the MD patients during
Normal condition
62
Mute Condition
A trend of increased global synchronisation strength was found in MD patients in the Mute
Condition (p = 0.10). For the between-group comparisons, the electrode pairs that had a pvalue under 0.05 in the index of phase synchronisation are between the left lateral prefrontal
areas and the right primary motor cortex (ROI 1 and ROI 4, p = 0.0254) and the right inferior
parietal areas (ROI 1 and ROI 6, p = 0.0362), between the right lateral prefrontal areas and
the left primary motor area (ROI 2 and ROI 3, p = 0.035) and the temporal areas (ROI 2 and
ROI 7, p = 0.0268), between the left primary motor and the temporal areas (ROI 3 and ROI 7,
p = 0.0272), and between the right inferior parietal areas and the temporal areas (ROI 6 and
ROI 7, p = 0.016). The MD patients had a higher degree of phase synchronisation between all
the abovementioned pairs of electrodes.
Figure 5
Mute condition
63
Delay Condition
A trend of increased global synchronisation strength was found in MD patients in the Delay
Condition (p = 0.17). For the between-group comparisons, the electrode pairs that had a pvalue under 0.05 in the index of phase synchronisation are between the left lateral prefrontal
areas and the right lateral premotor area (ROI 1 and ROI 4, p = 0.0058), and the right inferior
parietal areas (ROI 1 and ROI 6, 0.0348), between the frontal medial areas and the right
lateral premotor area (ROI 4 and ROI 8, p = 0.0346), and between the frontal medial areas
and the SMA (ROI 8 and ROI 9, p = 0.0326). The MD patients had a higher degree of phase
synchronisation between all the abovementioned pairs of electrodes.
Figure 6
Delay condition
64
Glove Condition
No difference in the global synchronisation strength was found between the healthy pianists
and the MD patients in the Glove Condition (p = 0.38). For the between-group comparisons,
the electrode pairs that had a p-value under 0.05 in the index of phase synchronisation are
between the right inferior parietal areas and the SMA (ROI 5 and ROI 9, p = 0.0272), and the
medial intraparietal areas (ROI 5 and ROI 10, p = 0.0138). The MD patients had a higher
degree of phase synchronisation between all the abovementioned pairs of electrodes.
Figure 7
Glove condition
65
Discussion
During all the conditions in this study, the MD patients showed deteriorated motor control
over the keyboard and a trend of increased phase synchronisation in several pairs of
electrodes compared to the healthy pianists. In this discussion, each condition will be
individually discussed, followed by a general conclusion drawing from the results of all the
conditions.
Normal Condition
Under the Normal condition, the patients showed increased phase synchronisation
particularly between the right anterior and the left primary motor cortex, the SMA, and the
right sensorimotor areas. Increased phase synchronisation also appeared between the left
anterior and the right sensorimotor areas. Our results are similar to previous studies showing
the abnormal functional connectivity at SMA and primary motor cortex in FHD (Jin et al.
2011a; Jin et al. 2011b; Melgari et al. 2013) and altered cortical pattern during complex
finger movements in writer's cramp (Havrankova et al. 2011). Furthermore, it has been
shown that the ipsilateral sensorimotor cortex was increasingly inhibited during the
acquisition phase of piano playing (Bangert and Altenmüller 2003), and the right anterior
frontal areas and temporal areas are of major importance for real and imagined perception of
melodic and harmonic pitch sequences. The increased phase synchronisation of the
abovementioned areas in patients might be a result of the lack of inhibition in the neural
network required for piano playing in MD patients. Alternatively, this general increase of
phase synchronisation can be interpreted as a compensatory change in the basal ganglia,
sensorimotor cortex, sensorimotor association areas and cerebellum in FHD during accurate,
individuated finger control (Moore et al. 2012).
In addition, the frontal-parietal network has been shown to be crucial for goal-directed, topdown attention reorientation in various sensory modalities (Corbetta and Shulman 2002;
Shomstein and Yantis 2006). Therefore an increase in the phase synchronisation might be an
indication of higher attentional demand required by the MD patients to support their control
of automatized motor execution.
Mute Condition
It is known that complete deprivation of auditory feedback does not affect the execution of
well-rehearsed motor sequences but the expressivity and control of pedalling of piano playing
in healthy pianists (Repp 1999). Several neuroimaging studies have also demonstrated that
healthy pianists showed similar cortical activation patterns for both the acoustic and mute
66
motion-related tasks (Bangert and Altenmüller 2003; Bangert et al. 2006; Lahav et al. 2007),
which well supports the hypothesis that in piano playing the neural substrates recruited for
the feed-forward auditory-motor coupling is engaged not only during listening to auditory
feedback but also when it is absent. Our behavioural data showed that the patients had motor
control deterioration during the Mute condition as compared to the Normal condition, which
was not the case in healthy pianists. A comparable study in which writer's cramp patients had
to write without visual feedback showed that although the patients' automatisation of the
writing movement was not impaired and various writing parameters were similar to those of
the control subjects, the patients were significantly slower than the controls with lower mean
vertical writing pressure (Chakarov et al., 2006). Our result is in line with this writer's cramp
study since we focus on the analyses of temporal deviation in our MD patients' fine motor
control. Regarding to the topographical distribution of the phase synchronisation differences,
most differences between our healthy pianists and MD patients lay in the increased phase
synchronisation between the auditory area and the bilateral fronto-central areas, primary
motor areas and sensorimotor areas. We interpret this as an altered pattern of auditory-motor
coupling in MD patients. This most probably is another manifestation of impaired feedforward control during piano playing during the absence of auditory feedback. Furthermore,
the increased phase synchronisation between the frontal areas and the auditory area in MD
patients might indicate an increased demand on the pitch memory (Zatorre et al. 1994) since
they cannot rely on the integration of proprioceptive information like the healthy pianists do
under the absence of auditory feedback.
Delay Condition
Delayed auditory feedback has been extensively employed in speech studies that focused on
auditory-motor integration mechanisms. The asynchrony between speech production and its
auditory feedback has been investigated in several neuroimaging studies by using several
types of altered auditory feedback and it has been demonstrated that compared to the speech
production under normal auditory feedback, delayed auditory feedback may bring increased
activity in bilateral temporo-parietal regions in healthy people compared to the tasks with
normal auditory feedback (Hashimoto and Sakai 2003; Watkins et al. 2005; Takaso, Eisner et
al. 2010). Similar to speech production, delayed auditory feedback has also been shown to
bring serious disruptions in the motor planning and cortical activations in expert music
performance (Pfordresher 2006; Pfordresher et al. 2014). According to our behavioural data,
the keystroke timing of both the healthy pianists and MD patients was severely disrupted by
the delayed auditory feedback. The phase synchronisation in our MD patients was increased
between the frontocentral area and the SMA and right M1, and between the left frontal and
the right M1 and right parietal area, which might reflect an increased effort and an altered
67
pattern for a condition that requires untrained sensorimotor integration in the MD patients.
Glove condition
The Glove condition in the present study is related to a very distinct phenomenon, which is
also a diagnostic criterion for dystonia termed “sensory trick” in various types of focal
dystonia. Tactile manipulation is known to modify (induce or attenuate) dystonic symptoms.
In some patients, the involuntary movements, abnormal postures or associated feelings of
pain can be reduced or eliminated by the application of a personalised repertoire of tactile
stimulation (Leis et al. 1992; Gómez-Wong et al. 1998; Schramm et al. 2007). Although the
clinical features of the sensory tricks have been well-documented, the physiological
mechanisms behind this phenomenon are still under discussion. A PET study (Naumann et
al. 2000) reported effects of the sensory trick on cortical activation patterns, showing that the
trick manoeuvres lead to an increased activation mainly in the superior and inferior parietal
cortex. Furthermore the trick also leads to decreased activation of the SMA and the primary
sensorimotor cortex. The authors suggested a model in which successful sensory tricks act as
perceptual dysbalance that mediate distinct sensorimotor transformations and result in the
correction of the head position. In the present study, although the MD patients did not benefit
significantly from the tactile change for improved piano playing, the pattern of phase
synchronisation was the most “normalised” and closest to the healthy pianists among all the
conditions, except between the SMA and the contralateral sensorimotor area, which is similar
to Naumann and colleagues' finding in cervical dystonia. Accordingly, we speculate that the
MD patients had a comparable response to the altered tactile feedback, which results in the
recruitment of a distinct functional neural network required for the new sensorimotor
integration.
The comparisons between all the conditions in the present study add to the existing literature
focusing on the task-specificity of the motor impairment in MD (ex. van der Steen et al.
2014) by showing that MD patients differ from the healthy pianists to a greater degree in
conditions that rely largely on the long-trained task-specific feed-forward control, such as the
Normal and Mute conditions. Therefore in the Delay condition, in which such long-trained
feed-forward control is severely interrupted, there were less overall compensatory processes.
The patients were not trained to play under such disturbing mismatch between the action and
sound production. Furthermore, we propose that the fact that the Glove condition brought
most pronounced effect on the phase synchronisation was because the tactile feedback was a
more salient feature (as compared to auditory feedback) throughout the task so it normalised
the degree of neural synchronisation most. Probably for this reason altered tactile feedback is
68
often used as a sensory trick in many forms of focal dystonia. The present results also
demonstrate a general problem of inhibition in MD, particularly on the ipsilateral areas,
which may further support the use of a recent intervention that employs bihemispherical
tDCS for MD patients (Furuya et al. 2014). Furthermore, there is ample evidence supporting
the major role of inhibitory processes in the synchronisation of oscillatory activities in taskand state-dependent way (Singer 2013). Therefore the present results can be interpreted as
sensory feedback-dependent inhibitory deficiency in MD. Our findings are also in line with
recent studies on WC (Delnooz et al. 2012; Delnooz et al. 2013). The fact that in WC
patients, increased dorsal premotor cortical activity was linked to imagined writing and
reduced connectivity between the superior parietal and dorsal precentral regions was found
during resting-state also showed the task-specific impairment in FHD. In conclusion,
although the statistical results were mostly uncorrected, our findings demonstrate that MD
patients have a trend of altered sensorimotor integration while performing an overtrained task
by showing the between-group differences in the functional networks under altered sensory
feedback in piano playing. Future studies are required to further investigate the altered
sensorimotor integration in MD under different sensory feedback.
69
6
Conclusions and Outlook
6.1 Conclusions
As mentioned in the Introduction, the aims of the current thesis were to (1) show the effect of
altered sensory feedbacks in MD in a more comprehensive way, and to (2) help to elucidate
the differences in long-range neural orchestration between the healthy pianists and MD
patients under different types of sensory feedback during piano playing.
The hypothesis for (1) was that altered auditory feedback and altered somatosensory feedback
may act as successful sensory tricks in MD. But the results from the behavioural study in this
thesis demonstrated that the altered sensory feedback did not bring any beneficial effect to the
fine motor control of our patients on a group analysis level. Both groups of participants had
deteriorated fine motor control under the delayed auditory feedback. Neither the AAF (either
MUTE or DELAY) nor the altered tactile feedback (GLOVE) acted as a successful sensory
trick and improved the fine motor control of pianists suffering from MD significantly.
Therefore the results were against our hypothesis. It should be mentioned, however, that one
individual suffering from focal dystonia benefitted from the MUTE condition and 3 out of 12
patients had significantly improved motor control under GLOVE condition. This points
toward the heterogeneity in neural and /or behavioural organisation of musician’s dystonia.
After concluding for the first aim, an EEG study was carried out for the second aim, with the
hypotheses that the degree of inter-regional phase synchronisation between the cortical
regions involved in the sensorimotor network is altered in MD patients, and the patterns of
such alteration are dependent on the sensory feedback. As a result, the comparison of EEG
70
data revealed that in MD patients, there were higher degrees of inter-regional phase
synchronisation between the frontal and parietal regions and between the temporal and
central regions in conditions that are relevant to the long-trained auditory-motor coupling
(normal auditory feedback and complete deprivation of auditory feedback). Importantly, such
abnormalities are decreased in conditions with delayed auditory feedback and altered tactile
feedback. These findings support the hypothesis that the impaired sensorimotor integration of
MD patients is speci fic to the type of overtrained task that the patients were trained for and
can be modi fied with altered sensory feedback.
The findings of these studies add to the previous research on the sensory deficits in MD, or in
focal dystonia in general. In the research field of focal dystonia, there is currently a lack of
neuroimaging studies related to the sensory deficits and task-specificity of the disorder.
Furthermore, the only neuroimaging study related to the sensor trick phenomenon was the
PET study published by Naumann and his colleagues (2000). The EEG study in the present
thesis enabled the precise monitor over the dynamics of neural network under various altered
auditory feedback conditions without the noise in fMRI studies, offered novel evidences for
the sensory feedback-dependent neural de-orchestration in MD.
To conclude, neither did the altered auditory feedback nor did the altered tactile feedback
employed in the present thesis improve MD patients’ symptoms. This project did not find a
successful sensory trick in MD. However, the evidence of feedback-depend long-range phase
synchronisation contributes to the basic research in the pathophysiology of MD, and it leads
to more studies in the sensorimotor integration and task-specificity of MD in near future.
6.2 Outlook
Behavioural Study. The findings imply that it might be necessary to employ more diverse
motor tasks/motor patterns for experimental material and more forms of altered auditory
feedback for the future behavioural studies. Although the Scale Analysis paradigm itself has
been proved to be a robust and objective measurement for quantifying dystonic symptoms
and it has been suggested that with MD the symptoms are more easily triggered by
scale/scale-like playing (see Rosenkranz et al. 2009 for using C major scale-like sequence as
their experimental material), the high heterogeneity and task-specificity of MD symptoms
makes it difficult to conclude the effect of a single motor pattern has a similar effect on all the
patients. It is similar in the case of the temporal asynchrony and types of delay for the altered
auditory feedback. More lengths of duration and more types of delayed auditory feedback
should be involved in future experiments (ex. random delay, adaptive delay), and even faster
71
tempi of playing would be preferred for MD symptoms are usually triggered by fast tempi.
Furthermore, more diverse paradigms than synchronisation or synchronisation-continuation
paradigms may also be considered in future experiments.
EEG phase synchronisation Study. The analysis of the altered neural network in FHD is
gaining its importance since the abnormal reorganisation of functional cortical networks in
FHD has been shown (ex. Jin et al. 2011; Moore et al. 2012). Studying how different parts of
the neural system are abnormally orchestrated together in terms of their temporal coordination can help us better understand the rich phenomenology of dystonia, and probably a
dynamic, systematic view of the disorder is more important than studying a single isolated
deficit in the whole system in the case of dystonia. The next step of analyses should be
focused solely on the patterns of local and long-range cortical dynamics of the healthy
pianists performing under different sensory feedback, so the further comparison between the
healthy controls and the patients can lead to more fruitful results.
Dystonia is a complex movement disorder and it can only be understood with a broader view
of how different parts of the neural system work together. MD, as a form of dystonia, is one
of the best examples of how complex the disorder is and it further provides us with invaluable
insights into the neuroscience of musical excellence in healthy expert musicians. Although
the mechanisms of sensory trick remain elusive, I hope the studies in this thesis can
contribute a tiny piece to the puzzle of the pathophysiology of dystonia.
72
7
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Affidavit
I herewith declare that I autonomously carried out the PhD-thesis entitled “Sensory Trick in
Musician’s Dystonia: the Role of Altered Sensory Feedback in Pianists’s 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, Hanover
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.
_______________________________
(place, date)
_______________________________
(signature)
93
Acknowledgement
This dissertation would not have been completed without the help of many people. On a
professional note, I would like to thank the following people:
Prof. Dr. med. Eckart Altenmüller, mein Doktorvater, for offering me this research project,
encouraging me, inspiring me and teaching me so many invaluable, unforgettable life lessons.
I am immensely indebted to his most positive influence on me which has transformed me
greatly. I would like to thank him for these wonderful years I had at IMMM, which is an
absolutely lovely working environment owing to his effort and which I treat as my beloved
home in Germany. I’d like to thank my co-supervisors as well: Prof. Dr. med. Karin
Weißenborn, Prof. Dr. rer. nat. Günter Reuter and Prof. Dr. Stefan Debener, who is really
knowledgeable on EEG.
My fabulous colleagues in our extended “global IMMM family”, especially Michael
Großbach, Maria Herrojo Ruiz, Shinichi Furuya, Yousreya Pölkner, Mee-Ling Eddy, Philipp
Heiß, André Lee, Marieke van der Steen, Britta Westner, Franziska Buttkus, and Julia
Tiedemann. Michael always offers immediate help with literally everything and has such a
great sense of humour. This thesis could not have been finished without his help. Maria is an
adorable lady, a role model of mine, saved me from so many EEG horrors and gave me so
much more insight into scientific research. Shinichi is also a role model of mine, I really
enjoy our conversations that would meander through neuroscience, piano music, career
planning and of course, East Asian lifestyles. Yousreya takes good care of me, a real mum of
the whole institute with such loving, considerate personalities. Mee-Ling has become my
younger sister in Hannover in a way, helped me with my EEG studies and motivated me with
her positive personality and infinite energy. Philipp helped me with the attentional foci
studies, and we certainly had a great time together. André is always there, a really considerate
friend to share my daily life and feelings with. Marieke and Britta are such fantastic people,
made me optimistic and calmed me down at every crucial moment of my final stage of PhD.
Franziska is such a great friend to chat about dystonia research and about our love for music
and arts, we had the most amazing winter with plenty of Glühwein and awesome film nights
during my first year here. Julia helped a lot with my settling down in Hannover.
I am also extremely grateful to the following people on a more personal note:
Christopher Oakden, for being there, reading/listening to my utterly pointless gibberish,
cheering me up, making me laugh, and being my wonderful distraction and driving force
during the later years of my PhD. Thank you so much for tolerating my awful piano playing
94
and helping me to improve it, for proofreading part of this thesis, for translating Schumann’s
quote at the beginning of this thesis and for recruiting healthy pianists for my experiments
(!!!). Your quasi-Crocodile Dundee status is undoubtedly most appreciated.
Periklis Akritidis, for everything we had and everything we have. Thank you for encouraging
me to come to Germany for my PhD and for supporting me at so many turning points of my
life ever since our most memorable hedgehog-hunting and 2-people-on-1-bike nights in our
good old starry Cambridge. Most importantly, I can never thank you enough for being my
constant source of inspiration and admiration, and for being the one and the only original Peri
in my life. Ευχαριστώ.
My best friends Marta Machala and Meng-Chia Lin for knowing me so well, sharing my life
and my deepest thoughts, and for encouraging me, bringing me so many fantastic surprises
and the most touching moments throughout these years. Thank you both for the enduring
friendship along my life’s journey.
My closest neuroscientist-psychiatrist group of friends: Jelena Škuljec, Refik Pul, Karelle
Bénardais, Lydia Timm, and Deepashri Agrawal-Kakde. I will always remember the great
time we had together. A particularly big “thank you” to dearest Jelena - you always manage
to light up my murky sky.
My best Taiwanese friends in Germany: Yulin Eva Shen, Jui-Lan Huang, Ping-Ping Tsai,
Veronica Lin and Michelle Cheng. Thank you so much for sharing my personal feelings and
supporting/opposing my crazy ideas. Without you girls I would certainly be completely “deTaiwanised”. It is great to feel that I am still connected to my beloved motherland.
Stefan Nilles and Sujed Soradaj, two of the kindest people I know in this world. I am really
grateful for your generosity, especially during my first 3 months in Hannover. I consider
myself to be extremely lucky to have met you two.
Amanda Yen, En-Jhih Hua, Chin-Ju Tsai and many of my old friends scattered around the
world. Thank you for supporting and entertaining me all the time.
Last but not least, I would like to thank my most beloved parents and grandpa. I would not be
sitting here and writing all these without the support of my family.
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Sensory Trick in Musician`s Dystonia

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