Neuroplastic Changes Following Brain Ischemia and their Contribution to Stroke Recovery: Novel Approaches in Neurorehabilitation

Ischemic damage to the brain triggers substantial reorganization of spared areas and pathways, which is associated with limited, spontaneous restoration of function. A better understanding of this plastic remodeling is crucial to develop more effective strategies for stroke rehabilitation. In this review article, we discuss advances in the comprehension of post-stroke network reorganization in patients and animal models. We first focus on rodent studies that have shed light on the mechanisms underlying neuronal remodeling in the perilesional area and contralesional hemisphere after motor cortex infarcts. Analysis of electrophysiological data has demonstrated brain-wide alterations in functional connectivity in both hemispheres, well beyond the infarcted area. We then illustrate the potential use of non-invasive brain stimulation (NIBS) techniques to boost recovery. We finally discuss rehabilitative protocols based on robotic devices as a tool to promote endogenous plasticity and functional restoration

A randomized clinical control study on the efficacy of three-dimensional upper limb robotic exoskeleton training in chronic stroke

Background : Although robotics assisted rehabilitation has proven to be effective in stroke rehabilitation, a limited functional improvements in Activities of Daily Life has been also observed after the administration of robotic training. To this aim in this study we compare the efficacy in terms of both clinical and functional outcomes of a robotic training performed with a multi-joint functional exoskeleton in goal-oriented exercises compared to a conventional physical therapy program, equally matched in terms of intensity and time. As a secondary goal of the study, it was assessed the capability of kinesiologic measurements—extracted by the exoskeleton robotic system—of predicting the rehabilitation outcomes using a set of robotic biomarkers collected at the baseline. Methods : A parallel-group randomized clinical trial was conducted within a group of 26 chronic post-stroke patients. Patients were randomly assigned to two groups receiving robotic or manual therapy. The primary outcome was the change in score on the upper extremity section of the Fugl-Meyer Assessment (FMA) scale. As secondary outcome a specifically designed bimanual functional scale, Bimanual Activity Test (BAT), was used for upper limb functional evaluation. Two robotic performance indices were extracted with the purpose of monitoring the recovery process and investigating the interrelationship between pre-treatment robotic biomarkers and post-treatment clinical improvement in the robotic group. Results : A significant clinical and functional improvements in both groups (p < 0.01) was reported. More in detail a significantly higher improvement of the robotic group was observed in the proximal portion of the FMA (p < 0.05) and in the reduction of time needed for accomplishing the tasks of the BAT (p < 0.01). The multilinear-regression analysis pointed out a significant correlation between robotic biomarkers at the baseline and change in FMA score (R2 = 0.91, p < 0.05), suggesting their potential ability of predicting clinical outcomes. Conclusion : Exoskeleton-based robotic upper limb treatment might lead to better functional outcomes, if compared to manual physical therapy. The extracted robotic performance could represent predictive indices of the recovery of the upper limb. These results are promising for their potential exploitation in implementing personalized robotic therapy. Clinical Trial Registration clinicaltrials.gov, NCT03319992 Unique Protocol ID: RH-UL-LEXOS-10. Registered 20.10.2017, https://clinicaltrials.gov/ct2/show/NCT0331999

The combined use of tDCS and other rehabilitation techniques to improve upper limb motor function after stroke

Transcranial Direct Current Stimulation (tDCS) has recently gained a lot of attention as a tool to modulate neuronal plasticity influencing motor learning processes and functional recovery after stroke (Schlaug & Renga 2008; Chisari et al., 2014). The main conceptual target is to use tDCS for normalizing imbalanced inter-hemispheric inhibition, increasing excitability of perilesional intact regions of the affected hemisphere with anodal stimulation and/or decreasing excitability of the contralesional hemisphere with cathodal stimulation (Celnik et al., 2009; Fregni et al., 2005; Hummel et al., 2005; Hummel & Cohen 2005; Hummel et al., 2006). First evidences demonstrated transient improvement of upper limb motor function after a single session of tDCS and some studies have suggested potentially cumulative effect of multiple sessions of tDCS in improving motor learning in healthy subjects and hand motor recovery in patients with stroke (Boggio et al., 2007; Reis et al., 2009). These findings allow to support the hypothesis that combining multi-sessions tDCS protocol with other upper limb rehabilitative techniques which use improve upper limb motor recovery after stroke (Wessel et al., 2015; Nair et al., 2008). At this purpose we overviewed studies in which a combined upper limb rehabilitative therapy including tDCS was administered to subacute or chronic stroke patients. Different treatments were associated with tDCS such as virtual reality-based therapy (VRT), robot assisted arm training (AT), constraint induced therapy (CIMT), or occupational therapy (OT). First evidences revealed that tDCS sessions can be administered simultaneously to conventional therapy sessions, and the mean tDCS treatment duration was about 10-15 sessions for 2-3 weeks. Most of these studies showed significant effects for experimental treatment groups versus control groups, evaluated with different clinical scales for upper limb motor function. All studies used functional scales to explore upper limb motor improvement, but e.g., Bolognini et al., (2011) also showed a neurophysiological correlate to identify reduction in interhemispheric inhibition probably mostly due of tDCS effects. Particularly effective was the association between tDCS and OT or CIMT (Nair et al., 2008; Lindberg et al., 2012; Bolognini et al., 2011). Conversely the other types of combined trails showed no significant or only preliminary results in upper limb outcome measures, probably due to a very small sample size. In this overview we conclude that tDCS can be considered an important tool to maximize the effects of traditional therapies for upper limb motor recovery, modulating the plasticity-dependent processes after stroke (Wessel et al., 2010). However it will be useful to clarify the timing and duration of tDCS administration protocols and how these parameters influence other therapies effects, in order to identify a useful combined upper limb rehabilitation strategy for stroke patients

NIBS-driven brain plasticity

Through plasticity the brain is able to change its function and to rearrange following injury or environmental changes. In recent years, it was shown that non-invasive brain stimulation (NIBS) techniques, especially transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) can contribute to understand how these plastic changes occur. Additionally, the literature suggests that TMS and tDCS may be used as interventional strategies to improve neurorehabilitation efforts and arguably recovery of motor function after brain lesions. This review focuses on the use of NIBS in experimental protocols for evaluation and modulation of brain plasticity, the factors contributing to the inter-individual variability of response, proposed mechanisms and difficulties in translating findings from small proof of principle studies through the pipeline to clinical practice