84 CHAPTER 4 in both scenarios. Importantly, we included manipulations of postural congruency and biomechanical complexity in our design to provide empirical evidence that participants used their own body as a reference during the task and, thus, that they did not identify hand laterality through purely visual strategies. The fact that both behavioural and cerebral responses were sensitive to these experimental manipulations confirms that participants employed an embodied strategy, which is corroborated by a large body of evidence. 21, 58, 59, 69, 70 Other features of our experimental design exclude that our findings are a generic consequence of disease-related factors, like peripheral changes and generic effects of symptoms as fatigue. For instance, participants responded flexing their toes, an experimental choice guided by the fact that the patients’ lower limbs were not affected by the disorder. Likewise, the selection of patients with unilateral symptoms, in combination with the inclusion of the factor laterality in our main analyses, provided a within-subject control, which allowed us to compare the affected and unaffected limb. The specificity of the cerebral effects to the affected upper extremity excludes that these effects stem from generic group differences in experienced task difficulty due to factors like fatigue. Conclusion and clinical implications Our findings suggest that maladaptive cerebral plasticity plays a role in residual motor dysfunction and subsequent persistent pain in NA. Our data localize cerebral changes in NA to visuomotor brain regions involved in sensorimotor integration, i.e. the right extrastriate cortex (close to the EBA) and the bilateral parieto-occipital sulcus. This may have important implications for treatment of NA, and possibly for other peripheral nerve disorders. For example, coordinative motor training with online visual feedback of the shoulder is one of the most effective treatments for residual complaints in NA. 1, 6 Likewise, visuomotor approaches targeting sensorimotor integration in other neural disorders include augmented (visual) feedback, action observation, and graded motor imagery. 179-181 Our findings suggest that a focus on visual feedback may further improve these treatments, especially for patients with motor dysfunction who experience persistent pain. Acknowledgements We thank our participants for their time and commitment to the study. We also thank Melissa Bakkenes and Eline van de Ven for their contribution to data collection, Paul Gaalman for his technical lab support, and Saskia Lassche, Fran Smulders and Juerd Wijntjes for their role in patient inclusion. Several authors of this publication are members of the Netherlands Neuromuscular Center (NL-NMD) and the European Reference Network for rare neuromuscular diseases (EURO-NMD). Funding This work was supported by the Prinses Beatrix Spierfonds [W.OR16-05]. The funder has had no role in development, execution of, or reporting on this study and its outcomes.
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