141 SUMMARY & GENERAL DISCUSSION 7 General discussion This thesis provides the first insight into the role of the central nervous system in the peripheral nerve disorder NA, and describes the first RCT aimed at improving residual complaints experienced by many patients. With that, this thesis combines a mechanistic (neuroimaging) perspective with a clinical trial, merging mechanism-based and evidencebased medicine. 193 This translational approach provides valuable insights into the cerebral underpinnings of residual motor dysfunction after peripheral nerve damage in NA, with important clinical implications. In this general discussion, I place the findings of the separate chapters in a broader perspective, to provide further insight into how the brain adapts to peripheral nerve injury in NA, how rehabilitation can aid recovery in NA, and to identify future directions. This discussion is structured around two main issues, relating to the two parts of this thesis, which are introduced below. Maladaptive cerebral plasticity was specific to the affected upper extremity, occurred in visuomotor brain regions, and appeared to be linked to clinical outcome. Importantly, with peripheral nerve recovery, activity in those same visuomotor brain areas increased towards normality. The fact that we found adaptations in visuomotor areas, but not in key (somato)motor/sensory regions, raises the question of what we can learn from the cerebral changes we found, but also from the changes that we did not find. The first section of this general discussion will therefore focus on Understanding the cerebral adaptations we did (not) find. A natural and crucial follow-up question in translational clinical research, pertains to the clinical relevance of our findings. Moreover, our findings suggest that specific, multidisciplinary rehabilitation could be further improved to increase treatment effects on cerebral mechanisms, as well as other clinical domains that did not show consistent treatment effects. The second section of this discussion will therefore revolve around the Clinical relevance of cerebral alterations and improving rehabilitation after peripheral nerve damage in NA. I will first evaluate the link between visuomotor cerebral adaptations and clinical outcome in NA. I will then discuss how our findings can be used to further improve rehabilitation for patients with NA. I will end this general discussion with some concluding remarks linking our findings to future directions. Understanding the cerebral adaptations we did (not) find In NA patients with residual motor dysfunction, both initial (mal)adaptation in response to peripheral nerve injury and recovery afterwards occurred in visuomotor brain regions. Based on the clinical observations6 that patients appear to be more impaired when performing trained movements vs. novel movements, and patients’ ability to regain motor control through coordinative training, we expected that adaptations would involve motor planning. As there was no previous literature on the central motor system in NA, we did not have any specific a priori hypotheses on whether patients would have (deficient) under-activation or (compensatory) over-activation, and whether potential alterations would occur in brain regions within and/or outside the core sensorimotor system. Based on early animal work99-106, 194 and later studies in humans with carpal tunnel syndrome, 43, 110, 111 upper limb amputation, 195 traumatic brachial plexus injury196-201 and other peripheral neuropathies, 162 we knew that peripheral nerve injury commonly elicits reorganization of somatic limb representations in primary motor and sensory areas as well as adaptations in other key motor and somatosensory areas such as the