Background: Disability resulting from stroke and traumatic brain injury represent the main causes of long-term complications in adults. There are no universally accepted treatments available to treat these conditions and the financial, personal, familial and social cost of these disabilities cannot be underestimated. Preliminary data from different laboratories have shown that it is possible to modulate plastic processes in the lesioned brain via pharmacological, or brain and somatosensory stimulation techniques. The purpose of this project is to identify mechanisms of stroke motor disability and characterize the most promising techniques to improve cortical plasticity in these patients to enhance functional recovery. Findings this year: It is known that in well-recovered stroke patients with recovered gross extant hand function, the degree of persistent fine motor impairment is directly related to aberrant neural signaling between ipsilesional and contralesional M1, or within ipsilesional M1 neurons that exert control over the affected hand muscles. However, the mechanisms of upper arm motor recovery in patients with poorer motor function are not well understood. In this study, we examined interhemispheric and intracortical inhibition in regions of M1 exerting control over paretic elbow flexor and extensor muscles. We recorded silent electromyography periods from contralateral and ipsilateral elbow flexors and extensors induced by TMS delivered concurrently with voluntary isometric contraction of the paretic biceps and triceps brachii muscles. The measures are analogous to measures of intracortical and interhemispheric inhibition, respectively, which can only be recorded from well-recovered patients. This allowed us to investigate the relationship between silent period features and motor recovery. We found that ipsilateral cortical silent periods were stronger in the paretic triceps than biceps brachii muscles, and significantly correlated with the magnitude of residual impairment (lower Fugl-Meyer scores). In contrast, contralateral cortical silent periods (i.e. - intracortical inhibition analogues) in the paretic biceps brachii, but not in the triceps, correlated positively with motor recovery (Fugl-Meyer scores) and negatively with spasticity (lower Modified Ashworth scores). These results suggest that interhemispheric inhibition and intracortical inhibition of paretic upper arm muscles relate to motor recovery in different ways. While interhemispheric inhibition may relate to poorer recovery, muscle-specific intracortical inhibition may relate to better outcome and lesser spasticity. This work provided new insight into the differential contribution of interhemispheric and intracortical inhibition to motor recovery and spasticity in stroke patients with severe motor dysfunction. We also investigated the mechanisms of motor skill learning impairments following stroke. Following initial learning of new skill, the memory becomes stabilized through a process known as consolidation. Further experience from engaging in the skill can lead to modification of the memory through a process known as reconsolidation. Yet, it is not clear whether reconsolidation involves the same brain network interactions as consolidation, or if they are independent to some degree. Here, we found that following stroke, patients displayed disrupted motor memory reconsolidation despite normal consolidation, relative to age-matched healthy controls. Furthermore, the degree of disruption to motor memory reconsolidation was explained by differences in the impact of brain lesions on brain network structure in individual patients. Specifically, greater interruption of a network spanning ventral premotor, primary motor, and posterior parietal cortex, all regions known to be important in skilled hand movements predicted poorer memory reconsolidation. In the future, can be used to guide interventional strategies to enhance brain function and resulting behavior in patients following stroke. Several findings emerged from international collaborations over the past year. A double-blinded, multi-center clinical trial (EVREST) investigated the use of non-immersive virtual reality as a rehabilitation strategy alternative to recreational therapy for motor recovery in acute stroke patients. In addition to conventional rehabilitation regiments, patient were randomly assigned to adjuvant therapy groups where they engaged in either a non-immersive, virtual reality-based upper limb exercises training program or regularly scheduled recreational activities (such as card or board games).Both groups showed an improvement in upper limb motor function following two weeks of therapy. No significant difference was found between the type of adjuvant therapy that was received (non-immersive virtual-reality-based training vs. regularly scheduled recreation activities).These findings suggest that the functional specificity and intensity of therapy post stroke appears to be more relevant to recovery than the technology platform. This suggests that simple, low-cost and widely available activities should be considered as options in settings where advanced technologies are not available, or cost-effective. Reliable predictors of motor improvement in individual patients after stroke are scarce. The upper extremity portion of the Fugl-Meyer Assessment (FMA) has been proposed as a tool for predicting recovery, with the expected gain being approximately 70% of the difference between the initial FMA score obtained from an individual soon after stroke and the maximum possible score (recovery-typical). However, a significant number of patients are unable to achieve this predicted recovery milestone, as they improve much less than expected (recovery-atypical). In collaboration with a group at the University of Geneva, we investigated the combined use of FMA scores and diffusion-weighted MRI data to predict recovery patterns in patients after stroke. We found that the estimated level of degeneration of the corticospinal tract is a useful indicator for determining if individual patients will follow recovery-typical or recovery-atypical patterns. We also determined that a more accurate projection for patients with more severe corticospinal tract degeneration measured 2 weeks after stroke is approximately a 30% gain in functional motor improvement. This result has now been independently validated in a larger a population of 63 stroke patients. In a collaborative study primarily performed at the University of Tubingen, we investigated the feasibility of using real-time functional MRI feedback to increase cortico-subcortical communication within the lesioned hemisphere of chronic stroke patients. The disruption of these anatomical pathways is related to the severity of upper limb motor impairments following stroke. Thus, augmentation of these pathways is likely to improve recovery profiles in these patients. Here, 3 out of 4 patients learned to voluntarily modulate cortico-subcortical connectivity as intended. These results suggest that training using real-time functional MRI feedback can be safely and effectively used to target cortico-subcortical information pathways following stroke.