Focal dystonia in musicians is one of the most important problems to solve in the field of musician’s medicine. Musicians suffering from the disorder are highly disabled professionally and the disorder often leads to the termination of their musical career.
The present thesis investigates functional effects of tDCS on fine motor control in musicians with focal hand dystonia. tDCS can modulate cortical excitability and is a non-invasive tool to guide neuroplasticity. As the specific pathophysiology of musician’s dystonia involves a loss of inhibition in the central nervous system and maladaptive plasticity, tDCS may offer new treatment options.
Three placebo-controlled and double-blind studies were conducted and are described in chapter 4. The results of the first study indicated that a single session of cathodal tDC-Stimulation over the primary motor cortex was not sufficient to facilitate fine motor control in guitarists suffering from musician’s dystonia. In the following experiments, tDCS was combined with a motor learning paradigm (consisting of a sensorimotor retraining at the piano) and both cathodal and anodal stimulation were applied (studies 2 and 3). Study 2 investigated the effects of one single session of tDCS-supported sensorimotor retraining in a group of pianists suffering from musician’s dystonia. No effects on fine motor control were found. Study 3 investigated the effect of a 5-day repeated tDCS-supported retraining in one single pianist with musician’s dystonia. Beneficial effects of daily repeated sessions of
sensorimotor retraining were found in all three stimulation conditions (anodal, cathodal and placebo). Anodal tDCS did not enhance retraining effects beyond placebo, but cathodal tDCS may have prolonged retraining effects.
Single session treatment
Why did the single application of tDCS combined with sensorimotor retraining in study 2 yield negative results? According to our hypothesis, we expected that cathodal tDCS of the primary motor cortex would be able to facilitate fine motor control through reducing motor cortex excitability in a group of professional guitarists with musician’s dystonia. A reduction of motor cortex excitability was assumed to improve fine motor control as it may support the decreased inhibitory functions in patients with focal dystonia. It was also expected that anodal and/or cathodal tDCS combined with a sensorimotor retraining would improve fine motor control through facilitated motor learning and by reducing motor cortex excitability during the learning paradigm. Since the acquisition of new motor skills is accompanied by changes of neuronal activity and excitability, we assumed that tDCS would be a promising tool to assist motor learning.
There are several possible reasons for the negative outcome of studies 1 and 2. Firstly, consideration must be given to the short intervention time, as this may provide an explanation for the results. One stimulation session of 20min, even if combined with retraining, does not seem sufficient to change the pathophysiological movement patterns in musician’s dystonia.
The “relearning” of new movement patterns on a behavioural level and on a neurophysiological level requires a certain minimum amount of time and/or session numbers.
Deep brain stimulation as it is applied in generalized dystonia requires several months to induce changes on the neurophysiological level (Ruge et al. 2009). This example demonstrates that time is needed to elicit long lasting changes in dystonia. Behavioural treatment approaches to musician’s dystonia aim to use neuroplastic learning principles of the central nervous system and naturally require at least a certain amount of practise (Jabusch et al. 2006). The hypothesis that tDCS-supported retraining might lead to more efficient and direct improvement after one retraining session was not verified.
A second explanation for the negative outcome may be the chosen stimulation area. The stimulation of the primary motor cortex only may be not sufficient to facilitate sensorimotor learning of new movement patterns in musician’s dystonia. Additional stimulation of pre-motor areas, supplemental pre-motor areas and visual areas (Antal et al. 2004, Antal et al. 2004) might elicit beneficial effects and could form the basis of future investigation. Stimulation of
the internal globus pallidus as carried out in the treatment of generalized dystonia and segmental dystonia has been shown to substantially improve symptoms in primary dystonia (Voges et al. 2010, Woehrle et al. 2009). In the case of focal and task-specific dystonia, this treatment can not be applied regularly, as it involves a very invasive and complex procedure.
A few studies deal with the effects of deep brain stimulation in writer’s cramp and report major improvements after stimulation (Cho et al. 2009; Fukaya et al. 2003). It is possible that transcranially applied direct current stimulation did not activate the cortico-subcortical structures necessary for improving fine motor control in the desired way.
Next to electrode positioning, current density is also known to influence the effects of tDCS.
Further studies on the effects of tDCS in musician’s dystonia should thus vary the current density to a certain degree. The used protocol of 0.057mA/cm2 is applied frequently in clinical studies and appears to be safe (see safety of tDCS, chapter 2). Current density should not be increased without careful consideration of safety aspects, especially when tDCS is applied to patients.
Another possible reason for the negative results of the single session treatment in studies 1 and 2 may lie in the specific pathophysiology of musician’s dystonia itself.
In healthy subjects, tDCS influences the after-effects of low-frequency repetitive TMS (rTMS) when it is applied prior to the rTMS (Siebner et al. 2004). After a preconditioning with anodal tDCS, thus increasing cortical excitability, the normal inhibitory after-effects of low-frequency rTMS were even enhanced. The mean amplitudes of motor evoked potentials (MEPs) were significantly reduced compared to the condition without preconditioning anodal tDCS. A preconditioning with cathodal tDCS produced the opposite effect. The low-frequency rTMS even resulted in an increased cortical excitability. The authors suggest that there are mechanisms of synaptic stabilization providing a “homeostatic”-like plasticity in the primary motor cortex in healthy subjects. These mechanisms are assumed to keep excitability levels within a useful dynamic range.
In patients with writer’s cramp, however, the described effects were absent (Quartarone et al.
2005). A preconditioning of the primary motor cortex with anodal tDCS did not enhance the inhibitory after-effects of 1 Hz rTMS in the patients. Also preconditioning cathodal tDCS did not influence the after-effects of 1 Hz rTMS. According to Quartarone and colleagues (2005), the homeostatic stabilization of plastic effects may be impaired in patients with focal dystonia. Moreover, they propose that a faulty homeostatic response to acute increases in corticospinal excitability favours maladaptive motor plasticity.
In this context, the most relevant result of Quartarone and colleagues (2005) was the complete lack of the normal inhibitory effect of cathodal tDCS on corticospinal excitability in the patients. Why did cathodal stimulation fail to influence cortical excitability? The researchers suggest that this result relates to the fact that tDCS is a “tonic” stimulation that can only bias the firing frequency and membrane potential of already active cells. Research results indicate that cathodal tDCS produces its effects by reducing ongoing levels of discharge and hyperpolarizing membrane potentials (Nitsche et al. 2000). The hyperpolarisation of a cell increases the chance of long-term depression of synapses (LTD, see also mechanisms of tDCS, chapter 2). Quartarone and colleagues argue that in patients with dystonia at rest the cell membrane potentials are already strongly hyperpolarized compared to healthy subjects.
Thus, cathodal tDCS is unable to decrease excitability any further so that amplitudes of MEPs are not changed in the patients. In contrast, anodal tDCS induces plastic effects as seen in healthy subjects because anodal stimulation is able to depolarize the neurons.
In our studies, we focused on the behavioural effects of treatment and investigated the fine motor control of patients directly after tDCS and retraining sessions at the musical instrument.
As focal dystonia in musicians is a task-specific disorder, symptoms occur only while the patients play their musical instrument. The investigation of fine motor control directly at the instrument requires specialisation and experience in the field of musicians’ medicine. In studies 2 and 3, fine motor control was measured by an objective tool developed for the quantification of musician’s dystonia in pianists, implemented at the Institute of Music Physiology and Musicians’ Medicine in Hanover (Jabusch et al. 2004). Our main focus in the experiments relating to this thesis was the careful investigation of behavioural effects directly after stimulation without any further distraction of the patients. Musicians with musician’s dystonia often report that the amelioration of symptoms after performing sensorimotor retraining or after other treatments is easily influenced by other stimuli. This might also be related to the sensory trick phenomenon (Schramm et al. 2004), which is characterized by a transient improvement of motor symptoms by a change in afferent sensory information.
For this reason it was decided not to include trancranial magnetic stimulation techniques (TMS). As we did not observe beneficial behavioural effects after tDCS, it would be interesting to investigate whether the normal inhibitory effects of cathodal tDCS take place in patients with musician’s dystonia or not. The use of transcranial magnetic stimulation would allow the measurement of physiological effects and could answer this question. Further studies investigating the effects of tDCS on musician’s dystonia should therefore include TMS-techniques in addition to behavioural measurements, if possible.
The altered response to tDCS in patients with focal dystonia compared to healthy subjects was only observed with cathodal stimulation. As described above, anodal stimulation effects are reported to be similar in both groups (Quartarone et al. 2005). According to our hypothesis, we expected anodal tDCS to facilitate motor learning of the musicians during the sensorimotor retraining in study 2. The lack of improvement of fine motor control after anodal tDCS-supported sensorimotor retraining in study 2 might be due to the previously described effects.
In the outpatient clinic of the Institute of Music Physiology and Musicians’ Medicine in Hanover we often observe that sensorimotor retraining elicits stronger effects when the affected musicians perform the retraining frequently. On the other hand, Boggio and colleagues (2007) found that daily repeated application of tDCS enhances the modulation of cortical excitability. For this reason we decided to conduct a study with daily repeated sessions of tDCS-supported retraining.
Repeated session treatment
In order to investigate effects of daily repeated tDCS-supported retraining on fine motor control in musician’s dystonia, we conducted a single case study with repeated treatment sessions. Daily repeated treatment sessions required the participating musician to spend a total of three weeks (3.5 hours a day) taking part in the experiment. For this reason we decided to conduct a single case study as a more efficient way of yielding first results about the effects of repeated tDCS-supported retraining sessions.
We observed that retraining resulted in beneficial effects on fine motor control in the reported patient, which was prolonged in the cathodal tDCS condition. Anodal tDCS did not enhance retraining effects beyond placebo. Improved fine motor control was found in all three stimulation conditions and was most pronounced immediately after treatment. Just 20 minutes of sensorimotor retraining per day led to a substantial improvement of symptoms in the reported patient, This result was rather unexpected but shows again the therapeutic option of behavioural treatment approaches to musician’s dystonia (see chapter 1, therapy of musician’s dystonia). The conclusions that can be drawn from the results of study 3 are of course limited since the effects of sensorimotor retraining will need to be investigated in a larger number of patients. In the reported patient, motor control deteriorated again during the follow-up (see Figure 1, page 67). Musicians with focal dystonia often report that the effects of retraining exercises are not stable and that symptoms deteriorate over time after the end of one practise session (Altenmüller 2009, personal communication). This phenomenon is a main reason why patients undergoing behavioural treatment often have to invest years of practise before
regaining stable motor control at their instrument. Studies investigating optimal retraining strategies in terms of efficiency are required. This is especially the case since many musicians prefer treatment options which include active involvement and a perceived self-control. As each musician experience slightly different symptoms, strategies and exercises should be defined and described in a way that is applicable to individual symptoms.
In study 3, the inter-treatment comparison suggests that cathodal tDCS may prolong retraining effects. The intended inhibitory effect of cathodal tDCS may have facilitated physiological inhibition in the reported patient and stabilized retraining effects. However, as a limitation of the results cumulative retraining effects in the cathodal stimulation week may have influenced the outcome. Cathodal tDCS was applied in the third study week, meaning that the reported patient had performed two weeks of tDCS-supported retraining already. However, to avoid any carry-over effect, an interval of at least 6 weeks was observed between treatment conditions. Again, studies on large numbers of patients with musician’s dystonia are needed to clarify effects of repeated cathodal tDCS on retraining.
General conclusion and outlook
To summarize previous studies investigating the effects of tDCS on patients with focal dystonia and the results of the present thesis, tDCS does not appear the most promising method to offer new therapeutic options in musician’s dystonia. However, the results from tDCS-studies help us to gain new insight into the pathophysiology of musician’s dystonia.
tDCS is a non-invasive method to induce cortical plasticity.
Other stimulation techniques as for example repetitive transcranial magnetic stimulation (rTMS) or random noise stimulation may constitute an interesting next step in focal dystonia research. The technique of rTMS in particular may yield beneficial effects on fine motor control in musician’s dystonia. Several researchers have investigated the effects of rTMS in patients with writer’s cramp and found promising results. Similar to tDCS, rTMS has been shown to increase or decrease the excitability of corticospinal or corticocortical pathways.
However, the after-effects of rTMS are also believed to occur in corticospinal pathways as is probably not be the case in long lasting effects of tDCS (Nitsche et al. 2003). The physiological changes induced by rTMS depend on the intensity of stimulation, coil orientation and frequency of stimulation. The underlying mechanisms are believed to be similar to long-term potentiation (LTP) and long-term depression (LTD) as is probably the case for tDCS.
In healthy subjects, low-frequency rTMS reduces cortical excitability in stimulated areas.
Similar to our hypothesis, research studies hypothesized that the modulating effects of rTMS offer a new perspective for the treatment of conditions characterized by alterations of cortical excitability. The effects of rTMS on patients with focal dystonia were investigated in several studies and yielded interesting results: Siebner and colleagues (1999) stimulated the motor cortex with a low-frequency rTMS in healthy subjects and in patients with writer’s cramp.
The authors aimed to reduce the abnormally enhanced excitability in the motor cortex of the patients and measured motor cortex excitability and handwriting abilities after rTMS. In a first experiment, Siebner and colleagues found that low-frequency rTMS resulted in a normalization of the deficient cortico-cortical inhibition in the patients without affecting the motor threshold. In a second experiment, cortical excitability was measured by a stimulus-response curve and by the post-excitatory silent period before and after subthreshold rTMS.
1Hz rTMS resulted in a significant prolongation of the post-excitatory silent period without affecting the stimulus-response curve in the patients. Behavioural tests in both experiments demonstrated a reduction of mean writing pressure which was related to a clear but transient improvement of handwriting in the patients. Authors concluded that rTMS may be able to reinforce deficient intracortical inhibition in the patients and may improve fine motor control temporarily in writer’s cramp. As we observed no beneficial behavioural effects of the DC-stimulation used in our experiments, there is obviously a crucial difference between the two stimulation techniques concerning the susceptibility of the stimulation in focal dystonia. To our knowledge, the application of rTMS on patients with musician’s dystonia as a special form of focal dystonia has not yet been investigated. A combination of low frequency rTMS supporting a motor learning paradigm on patients with musician’s dystonia may yield particularly interesting results. As described above, there is some evidence for a reinforced deficient intracortical inhibition after low frequency rTMS in patients with focal dystonia. A combination of sensorimotor retraining exercises and reinforced inhibition as undertaken in our experiments may be a rewarding approach in attempting to improve current treatment options for musician’s dystonia. Facilitated sensorimotor learning in affected musicians may result in the improved efficiency of retraining exercises. Stabilizing the retraining effects over time through prolonging them with rTMS-treatment could add a wonderful new therapy option for affected musicians.
Treatment of patients with musician’s dystonia in general is still a challenge (Frucht et al.
2001, Altenmüller et al. 2010). Many of the available medical approaches are only moderately
effective, and other options have yet to be developed. Behavioural therapies and interdisciplinary strategies combining pharmacological, behavioural and perhaps electrophysiological methods are promising, but the different approaches need to be evaluated and long-term effects are still unknown (Altenmüller et al. 2010). More research in this field is needed.
If external factors such as disadvantageous practise habits, exaggerated perfectionism and anxiety play a role in the multifactor network influencing focal dystonia, this should be addressed also for prevention. The education system for musicians like music schools and music academies should rather cultivate a playful attitude towards making music, and replace the fascination of mere perfection and virtuosity by the joy of emotional communication shared by the audience and the musicians (Altenmüller et al. 2009).
Acknowledgements
My special thanks go to Prof. Dr. med. Altenmüller. He advised me in his friendly and humorous way during each phase of the PhD. I always liked the atmosphere at the Institute of Music Physiology and Musician’s Medicine which is created by him. I would like to thank Prof. Altenmüller especially for his prompt help when it was necessary. His attitude to feel responsible for his students and co-workers is extraordinary.
I would also like to thank my Co-Supervisors Prof. Dr. med Dengler and Prof. Dr. Fahlke for their constructive comments and fair questions during the supervisor meetings of the ZSN.
I am also very grateful to our collaborators Dr. rer. nat. Michael Nitsche and Prof. Walter Paulus from Göttingen. They advised us in all questions concerning the stimulation parameters of the experiments and they were always encouraging and extraordinary kind.
My colleagues at the Institute of Music Physiology and Musician’s Medicine were very important to me during the last years. First of all, I would like to thank Prof. Dr. med. Hans-Christian Jabusch for his great advice and brilliant input in all aspects of my project. He especially helped to analyse the data of the experiments 2 and 3 and he supervised me how to write scientific papers.
Special thanks also go to my colleague Dr. Michael Großbach, who was always open to questions and discussions about my experiments and focal dystonia in general. His steady motivation and his friendly way of helping are amazing.
I would like to thank Volker Baur for his unceasing support and his competent input to the
I would like to thank Volker Baur for his unceasing support and his competent input to the