145 SUMMARY & GENERAL DISCUSSION 7 factors. An unexpected finding of this thesis was that NA patients showed increased brain activity in visuomotor brain regions from baseline to follow-up independent of the type of treatment they received, and despite the fact that specific rehabilitation elicited greater clinical improvement than usual care. This raises the question of how specific rehabilitation mediates clinical outcome. One possible answer is that it may be influencing other processes or structures. First, we can speculate about what cerebral processes, other than the visuomotor processes we now know to be altered in NA, may be involved. Candidates include cognitive and emotional processes related to self-management, 220 which are trained through occupational therapy as a core aspect of the program. 36 As discussed in the previous section, changes in NA may also occur in the core sensorimotor system: specific rehabilitation may be improving clinical outcome by influencing primary sensorimotor, or other, cerebral processes that we did not (sufficiently) probe with our current paradigm. To study different aspects and stages of motor control, future work could apply approaches that are complementary to the one we used here. Some potential directions have been mentioned in the first section of this general discussion. Alternative neuroimaging techniques could improve ecological validity and temporal resolution. Motor execution and imagery tasks that involve reaching movements, could similarly improve ecological validity and could be used to study primary sensorimotor processes. Moreover, motor execution tasks enable the study of different aspects and stages of motor control in NA. By manipulating action feedback and execution (e.g. through perturbations or passive movement), it is possible to study processing and integration of afferent feedback across sensory modalities (i.e. visual, proprioceptive). 147, 209-215, 217 Second, while our focus so far has been on cerebral (mal)adaptations, different structures of the (central) nervous system may also be involved. The spinal cord, brainstem, and subcortical structures are important parts of the sensorimotor system that process both afferent feedback and efferent motor signals. 208, 221 Across these levels, (mal)adaptations, with functional consequences, have been reported in response to peripheral nerve injury. 12, 222, 223 It is possible that similar changes occur in NA, and that specific rehabilitation mediates clinical outcome through such mechanisms. Future studies could investigate whether these structures are also involved in persistent motor dysfunction in NA. Likewise, peripheral factors evidently influence (motor) outcome. It is however notoriously difficult to quantify peripheral factors in NA, 6 posing a challenge for future studies looking into the role these factors play in (lack of) functional recovery. Another important question that emerges from the discrepancy between clinical and cerebral findings, is how patients’ visuomotor activity patterns can recover towards normality without treatment that is specifically targeting these cerebral processes. To answer that question, we can expand on observations made in chapter 6. In recent years, awareness about and recognition of NA has improved in the Netherlands, and as a result the time between NA onset and referral to our plexus clinic has reduced substantially (as illustrated by the difference in median time since onset between chapters 3 (16 months) and 4 (8 months), with data collection occurring between 2015-2017 and 2018-2020, respectively). Since patients in our fMRI studies (chapters 4 and 6) were seen at an early disease stage, natural recovery will have inevitably played a role, more so than we anticipated when designing the RCT in 2016. The fact that brain activity increased towards normality, even though treatment
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